Molecules haveing pesticidal utiliy and intermediates, compositions and processes related thereto

ABSTRACT

This disclosure relates to the field of molecules having pesticidal utility against pests in Phyla Arthropoda, Mollusca, and Nematoda, processes to produce such molecules, intermediates used in such processes, pesticidal compositions containing such molecules, and processes of using such pesticidal compositions against such pests. These pesticidal compositions may be used, for example, as acaricides, insecticides, miticides, molluscicides, and nematicides. This document discloses molecules having the following formula (“Formula One”).

CROSS-REFERENCES TO RELATED APPLICATIONS

This Application is a continuation of, and claims the benefit of, U.S.nonprovisional application Ser. No. 15/727,878, which was filed Oct. 9,2017, and is now allowed, and which claims the benefit of, and priorityfrom, U.S. provisional applications Ser. Nos. 62/407,092 and 62/407,118;all of which were filed on Oct. 12, 2016. The entire contents of all ofthe above-identified applications are hereby incorporated by referenceinto this Application.

FIELD OF THIS DISCLOSURE

This disclosure relates to the field of molecules having pesticidalutility against pests in Phyla Arthropoda, Mollusca, and Nematoda,processes to produce such molecules, intermediates used in suchprocesses, pesticidal compositions containing such molecules, andprocesses of using such pesticidal compositions against such pests.These pesticidal compositions may be used, for example, as acaricides,insecticides, miticides, molluscicides, and nematicides.

BACKGROUND OF THIS DISCLOSURE

“Many of the most dangerous human diseases are transmitted by insectvectors” (Rivero et al.). “Historically, malaria, dengue, yellow fever,plague, filariasis, louse-borne typhus, trypanomiasis, leishmaniasis,and other vector borne diseases were responsible for more human diseaseand death in the 17^(th) through the early 20^(th) centuries than allother causes combined” (Gubler). Vector-borne diseases are responsiblefor about 17% of the global parasitic and infectious diseases. Malariaalone causes over 800,000 deaths a year, 85% of which occur in childrenunder five years of age. Each year there are about 50 to about 100million cases of dengue fever. A further 250,000 to 500,000 cases ofdengue hemorrhagic fever occur each year (Matthews). Vector controlplays a critical role in the prevention and control of infectiousdiseases. However, insecticide resistance, including resistance tomultiple insecticides, has arisen in all insect species that are majorvectors of human diseases (Rivero et al.). Recently, more than 550arthropod species have developed resistance to at least one pesticide(Whalon et al.). Furthermore, the cases of insect resistance continue toexceed by far the number of cases of herbicide and fungicide resistance(Sparks et al.).

Each year insects, plant pathogens, and weeds, destroy more than 40% ofall food production. This loss occurs despite the application ofpesticides and the use of a wide array of non-chemical controls, suchas, crop rotations, and biological controls. If just some of this foodcould be saved, it could be used to feed the more than three billionpeople in the world who are malnourished (Pimental).

Plant parasitic nematodes are among the most widespread pests, and arefrequently one of the most insidious and costly. It has been estimatedthat losses attributable to nematodes are from about 9% in developedcountries to about 15% in undeveloped countries. However, in the UnitedStates of America a survey of 35 States on various crops indicatednematode-derived losses of up to 25% (Nicol et al.).

It is noted that gastropods (slugs and snails) are pests of lesseconomic importance than other arthropods or nematodes, but in certainplaces, they may reduce yields substantially, severely affecting thequality of harvested products, as well as, transmitting human, animal,and plant diseases. While only a few dozen species of gastropods areserious regional pests, a handful of species are important pests on aworldwide scale. In particular, gastropods affect a wide variety ofagricultural and horticultural crops, such as, arable, pastoral, andfiber crops; vegetables; bush and tree fruits; herbs; and ornamentals(Speiser).

Termites cause damage to all types of private and public structures, aswell as to agricultural and forestry resources. In 2005, it wasestimated that termites cause over US$50 billion in damage worldwideeach year (Korb).

Consequently, for many reasons, including those mentioned above, thereis an on-going need for the costly (estimated to be about US$256 millionper pesticide in 2010), time-consuming (on average about 10 years perpesticide), and difficult, development of new pesticides (CropLifeAmerica).

CERTAIN REFERENCES CITED IN THIS DISCLOSURE

CropLife America, The Cost of New Agrochemical Product Discovery,Development & Registration, and Research & Development predictions forthe Future, 2010.

Drewes, M., Tietjen, K., Sparks, T. C., High-Throughput Screening inAgrochemical Research, Modern Methods in Crop Protection Research, PartI, Methods for the Design and Optimization of New Active Ingredients,Edited by Jeschke, P., Kramer, W., Schirmer, U., and Matthias W., p.1-20, 2012.

Gubler, D., Resurgent Vector-Borne Diseases as a Global Health Problem,Emerging Infectious Diseases, Vol. 4, No. 3, p. 442-450, 1998.

Korb, J., Termites, Current Biology, Vol. 17, No. 23, 2007.

Matthews, G., Integrated Vector Management: Controlling Vectors ofMalaria and Other Insect Vector Borne Diseases, Ch. 1, p. 1, 2011.

Nicol, J., Turner S., Coyne, L., den Nijs, L., Hocksland, L.,Tahna-Maafi, Z., Current Nematode Threats to World Agriculture, Genomicand Molecular Genetics of Plant—Nematode Interactions, p. 21-43, 2011.

Pimental, D., Pest Control in World Agriculture, AgriculturalSciences—Vol. II, 2009.

Rivero, A., Vezilier, 3., Weill, M., Read, A., Gandon, S., InsectControl of Vector-Borne Diseases: When is Insect Resistance a Problem?Public Library of Science Pathogens, Vol. 6, No. 8, p. 1-9, 2010.

Sparks T. C., Nauen R., IRAC: Mode of action classification andinsecticide resistance management, Pesticide Biochemistry and Physiology(2014) available online 4 Dec. 2014.

Speiser, B., Molluscicides, Encyclopedia of Pest Management, Ch. 219, p.506-508, 2002.

Whalon, M., Mota-Sanchez, D., Hollingworth, R., Analysis of GlobalPesticide Resistance in Arthropods, Global Pesticide Resistance inArthropods, Ch. 1, p. 5-33, 2008.

DEFINITIONS USED IN THIS DISCLOSURE

The examples given in these definitions are generally non-exhaustive andmust not be construed as limiting this disclosure. It is understood thata substituent should comply with chemical bonding rules and stericcompatibility constraints in relation to the particular molecule towhich it is attached. These definitions are only to be used for thepurposes of this disclosure.

The phrase “active ingredient” means a material having activity usefulin controlling pests, and/or that is useful in helping other materialshave better activity in controlling pests, examples of such materialsinclude, but are not limited to, acaricides, algicides, antifeedants,avicides, bactericides, bird repellents, chemosterilants, fungicides,herbicide safeners, herbicides, insect attractants, insect repellents,insecticides, mammal repellents, mating disrupters, molluscicides,nematicides, plant activators, plant growth regulators, rodenticides,synergists, and virucides (see alanwood.net). Specific examples of suchmaterials include, but are not limited to, the materials listed inactive ingredient group alpha.

The phrase “active ingredient group alpha” (hereafter “AIGA”) meanscollectively the following materials:

(1) (3-ethoxypropyl)mercury bromide, 1,2-dibromoethane,1,2-dichloroethane, 1,2-dichloropropane, 1,3-dichloropropene, 1-MCP,1-methylcyclopropene, 1-naphthol, 2-(octylthio)ethanol, 2,3,3-TPA,2,3,5-tri-iodobenzoic acid, 2,3,6-TBA, 2,4,5-T, 2,4,5-TB, 2,4,5-TP,2,4-D, 2,4-DB, 2,4-DEB, 2,4-DEP, 2,4-DES, 2,4-DP, 2,4-MCPA, 2,4-MCPB,2iP, 2-methoxyethylmercury chloride, 2-phenylphenol, 3,4-DA, 3,4-DB,3,4-DP, 3,6-dichloropicolinic acid, 4-aminopyridine, 4-CPA, 4-CPB,4-CPP, 4-hydroxyphenethyl alcohol, 8-hydroxyquinoline sulfate,8-phenylmercurioxyquinoline, abamectin, abamectin-aminomethyl, abscisicacid, ACC, acephate, acequinocyl, acetamiprid, acethion, acetochlor,acetofenate, acetophos, acetoprole, acibenzolar, acifluorfen, aclonifen,ACN, acrep, acrinathrin, acrolein, acrylonitrile, acypetacs,afidopyropen, afoxolaner, alachlor, alanap, alanycarb, albendazole,aldicarb, aldicarb sulfone, aldimorph, aldoxycarb, aldrin, allethrin,allicin, allidochlor, allosamidin, alloxydim, allyl alcohol, allyxycarb,alorac, alpha-cypermethrin, alpha-endosulfan, alphamethrin, altretamine,aluminium phosphide, aluminum phosphide, ametoctradin, ametridione,ametryn, ametryne, amibuzin, amicarbazone, amicarthiazol, amidithion,amidoflumet, amidosulfuron, aminocarb, aminocyclopyrachlor,aminopyralid, aminotriazole, amiprofos-methyl, amiprophos,amiprophos-methyl, amisulbrom, amiton, amitraz, amitrole, ammoniumsulfamate, amobam, amorphous silica gel, amorphous silicon dioxide,ampropylfos, AMS, anabasine, ancymidol, anilazine, anilofos, anisuron,anthraquinone, antu, apholate, aramite, arprocarb, arsenous oxide,asomate, aspirin, asulam, athidathion, atraton, atrazine, aureofungin,avermectin B1, AVG, aviglycine, azaconazole, azadirachtin, azafenidin,azamethiphos, azidithion, azimsulfuron, azinphosethyl, azinphos-ethyl,azinphosmethyl, azinphos-methyl, aziprotryn, aziprotryne, azithiram,azobenzene, azocyclotin, azothoate, azoxystrobin, bachmedesh, barban,barbanate, barium hexafluorosilicate, barium polysulfide, bariumsilicofluoride, barthrin, basic copper carbonate, basic copper chloride,basic copper sulfate, BCPC, beflubutamid, benalaxyl, benalaxyl-M,benazolin, bencarbazone, benclothiaz, bendaqingbingzhi, bendiocarb,bendioxide, benefin, benfluralin, benfuracarb, benfuresate,benmihuangcaoan, benodanil, benomyl, benoxacor, benoxafos, benquinox,bensulfuron, bensulide, bensultap, bentaluron, bentazon, bentazone,benthiavalicarb, benthiazole, benthiocarb, bentranil, benzadox,benzalkonium chloride, benzamacril, benzamizole, benzamorf, benzenehexachloride, benzfendizone, benzimine, benzipram, benzobicyclon,benzoepin, benzofenap, benzofluor, benzohydroxamic acid, benzomate,benzophosphate, benzothiadiazole, benzovindiflupyr, benzoximate,benzoylprop, benzthiazuron, benzuocaotong, benzyl benzoate,benzyladenine, berberine, beta-cyfluthrin, beta-cypermethrin,bethoxazin, BHC, bialaphos, bicyclopyrone, bifenazate, bifenox,bifenthrin, bifujunzhi, bilanafos, binapacryl, bingqingxiao,bioallethrin, bioethanomethrin, biopermethrin, bioresmethrin, biphenyl,bisazir, bismerthiazol, bismerthiazol-copper, bisphenylmercurymethylenedi(x-naphthalene-y-sulphonate), bispyribac, bistrifluron,bisultap, bitertanol, bithionol, bixafen, blasticidin-S, borax, Bordeauxmixture, boric acid, boscalid, BPPS, brassinolide, brassinolide-ethyl,brevicomin, brodifacoum, brofenprox, brofenvalerate, broflanilide,brofluthrinate, bromacil, bromadiolone, bromchlophos, bromethalin,bromethrin, bromfenvinfos, bromoacetamide, bromobonil, bromobutide,bromociclen, bromocyclen, bromo-DDT, bromofenoxim, bromofos,bromomethane, bromophos, bromophos-ethyl, bromopropylate, bromothalonil,bromoxynil, brompyrazon, bromuconazole, bronopol, BRP, BTH, bucarpolate,bufencarb, buminafos, bupirimate, buprofezin, Burgundy mixture,busulfan, busulphan, butacarb, butachlor, butafenacil, butam, butamifos,butane-fipronil, butathiofos, butenachlor, butene-fipronil, butethrin,buthidazole, buthiobate, buthiuron, butifos, butocarboxim, butonate,butopyronoxyl, butoxycarboxim, butralin, butrizol, butroxydim, buturon,butylamine, butylate, butylchlorophos, butylenefipronil, cacodylic acid,cadusafos, cafenstrole, calciferol, calcium arsenate, calcium chlorate,calcium cyanamide, calcium cyanide, calcium polysulfide, calvinphos,cambendichlor, camphechlor, camphor, captafol, captan, carbam,carbamorph, carbanolate, carbaril, carbaryl, carbasulam, carbathion,carbendazim, carbendazol, carbetamide, carbofenotion, carbofuran, carbondisulfide, carbon tetrachloride, carbonyl sulfide, carbophenothion,carbophos, carbosulfan, carboxazole, carboxide, carboxin, carfentrazone,carpropamid, cartap, carvacrol, carvone, CAVP, CDAA, CDEA, CDEC,cellocidin, CEPC, ceralure, cerenox, cevadilla, Cheshunt mixture,chinalphos, chinalphosmethyl, chinomethionat, chinomethionate,chiralaxyl, chitosan, chlobenthiazone, chlomethoxyfen, chloralose,chloramben, chloramine phosphorus, chloramphenicol, chloraniformethan,chloranil, chloranocryl, chlorantraniliprole, chlorazifop, chlorazine,chlorbenside, chlorbenzuron, chlorbicyclen, chlorbromuron, chlorbufam,chlordane, chlordecone, chlordimeform, chlorempenthrin, chloretazate,chlorethephon, chlorethoxyfos, chloreturon, chlorfenac, chlorfenapyr,chlorfenazole, chlorfenethol, chlorfenidim, chlorfenprop, chlorfenson,chlorfensulphide, chlorfenvinphos, chlorfenvinphos-methyl,chlorfluazuron, chlorflurazole, chlorflurecol, chlorfluren,chlorflurenol, chloridazon, chlorimuron, chlorinate, chlor-IPC,chlormephos, chlormequat, chlormesulone, chlormethoxynil, chlornidine,chlornitrofen, chloroacetic acid, chlorobenzilate,chlorodinitronaphthalenes, chlorofénizon, chloroform, chloromebuform,chloromethiuron, chloroneb, chlorophacinone, chlorophos, chloropicrin,chloropon, chloroprallethrin, chloropropylate, chlorothalonil,chlorotoluron, chloroxifenidim, chloroxuron, chloroxynil, chlorphonium,chlorphoxim, chlorprazophos, chlorprocarb, chlorpropham, chlorpyrifos,chlorpyrifos-methyl, chlorquinox, chlorsulfuron, chlorthal,chlorthiamid, chlorthiophos, chlortoluron, chlozolinate, chltosan,cholecalciferol, choline chloride, chromafenozide, cicloheximide,cimectacarb, cimetacarb, cinerin I, cinerin II, cinerins, cinidon-ethyl,cinmethylin, cinosulfuron, cintofen, ciobutide, cisanilide, cismethrin,clacyfos, clefoxydim, clenpirin, clenpyrin, clethodim, climbazole,cliodinate, clodinafop, cloethocarb, clofencet, clofenotane,clofentezine, clofenvinfos, clofibric acid, clofop, clomazone,clomeprop, clonitralid, cloprop, cloproxydim, clopyralid, cloquintocet,cloransulam, closantel, clothianidin, clotrimazole, cloxyfonac,cloxylacon, clozylacon, CMA, CMMP, CMP, CMU, codlelure, colecalciferol,colophonate, copper 8-quinolinolate, copper acetate, copperacetoarsenite, copper arsenate, copper carbonate, basic, copperhydroxide, copper naphthenate, copper oleate, copper oxychloride, coppersilicate, copper sulfate, copper sulfate, basic, copper zinc chromate,coumachlor, coumafène, coumafos, coumafuryl, coumaphos, coumatetralyl,coumethoxystrobin, coumithoate, coumoxystrobin, CPMC, CPMF, CPPC,credazine, cresol, cresylic acid, crimidine, crotamiton, crotoxyfos,crotoxyphos, crufomate, cryolite, cue-lure, cufraneb, cumyleron,cumyluron, cuprobam, cuprous oxide, curcumenol, CVMP, cyanamide,cyanatryn, cyanazine, cyanofenphos, cyanogen, cyanophos, cyanthoate,cyantraniliprole, cyanuric acid, cyazofamid, cybutryne, cyclafuramid,cyclanilide, cyclaniliprole, cyclethrin, cycloate, cycloheximide,cycloprate, cycloprothrin, cyclopyrimorate, cyclosulfamuron, cycloxydim,cycluron, cyenopyrafen, cyflufenamid, cyflumetofen, cyfluthrin,cyhalodiamide, cyhalofop, cyhalothrin, cyhexatin, cymiazole, cymoxanil,cyometrinil, cypendazole, cypermethrin, cyperquat, cyphenothrin,cyprazine, cyprazole, cyproconazole, cyprodinil, cyprofuram, cypromid,cyprosulfamide, cyromazine, cythioate, cytrex, daimuron, dalapon,daminozide, dayoutong, dazomet, DBCP, d-camphor, DCB, DCIP, DCPA(Japan), DCPA (USA), DCPTA, DCU, DDD, DDPP, DDT, DDVP, debacarb,decafentin, decamethrin, decarbofuran, deet, dehydroacetic acid,deiquat, delachlor, delnav, deltamethrin, demephion, demephion-O,demephion-S, demeton, demeton-methyl, demeton-O, demeton-O-methyl,demeton-S, demeton-S-methyl, demeton-S-methyl sulphone,demeton-S-methylsulphon, DEP, depalléthrine, derris, desmedipham,desmetryn, desmetryne, d-fanshiluquebingjuzhi, diafenthiuron, dialifor,dialifos, diallate, di-allate, diamidafos, dianat, diatomaceous earth,diatomite, diazinon, dibrom, dibutyl phthalate, dibutyl succinate,dicamba, dicapthon, dichlobenil, dichlobentiazox, dichlofenthion,dichlofluanid, dichlone, dichloralurea, dichlorbenzuron, dichlorfenidim,dichlorflurecol, dichlorflurenol, dichlormate, dichlormid,dichloromethane, dichlorophen, dichlorprop, dichlorprop-P, dichlorvos,dichlozolin, dichlozoline, diclobutrazol, diclocymet, diclofop,diclomezine, dicloran, dicloromezotiaz, diclosulam, dicofol, dicophane,dicoumarol, dicresyl, dicrotophos, dicryl, dicumarol, dicyclanil,dicyclonon, dieldrin, dienochlor, diethamquat, diethatyl, diethion,diéthion, diethofencarb, dietholate, diéthon, diethyl pyrocarbonate,diethyltoluamide, difenacoum, difenoconazole, difenopenten, difenoxuron,difenzoquat, difethialone, diflovidazin, diflubenzuron, diflufenican,diflufenicanil, diflufenzopyr, diflumetorim, dikegulac, dilor, dimatif,dimefluthrin, dimefox, dimefuron, dimehypo, dimepiperate, dimetachlone,dimetan, dimethacarb, dimethachlone, dimethachlor, dimethametryn,dimethenamid, dimethenamid-P, dimethipin, dimethirimol, dimethoate,dimethomorph, dimethrin, dimethyl carbate, dimethyl disulfide, dimethylphthalate, dimethylvinphos, dimetilan, dimexano, dimidazon,dimoxystrobin, dimpylate, dimuron, dinex, dingjunezuo, diniconazole,diniconazole-M, dinitramine, dinitrophenols, dinobuton, dinocap,dinocap-4, dinocap-6, dinocton, dinofenate, dinopenton, dinoprop,dinosam, dinoseb, dinosulfon, dinotefuran, dinoterb, dinoterbon,diofenolan, dioxabenzofos, dioxacarb, dioxathion, dioxation, diphacin,diphacinone, diphenadione, diphenamid, diphenamide, diphenyl sulfone,diphenylamine, diphenylsulphide, diprogulic acid, dipropalin,dipropetryn, dipterex, dipymetitrone, dipyrithione, diquat, disodiumtetraborate, disosultap, disparlure, disugran, disul, disulfiram,disulfoton, ditalimfos, dithianon, dithicrofos, dithioether,dithiométon, dithiopyr, diuron, dixanthogen, d-limonene, DMDS, DMPA,DNOC, dodemorph, dodicin, dodine, dofenapyn, doguadine, dominicalure,doramectin, DPC, drazoxolon, DSMA, d-trans-allethrin,d-trans-resmethrin, dufulin, dymron, EBEP, EBP, ebufos, ecdysterone,echlomezol, EDB, EDC, EDDP, edifenphos, eglinazine, emamectin, EMPC,empenthrin, enadenine, endosulfan, endothal, endothall, endothion,endrin, enestroburin, enilconazole, enoxastrobin, ephirsulfonate, EPN,epocholeone, epofenonane, epoxiconazole, eprinomectin, epronaz,epsilon-metofluthrin, epsilon-momfluorothrin, EPTC, erbon,ergocalciferol, erlujixiancaoan, esdépalléthrine, esfenvalerate, ESP,esprocarb, etacelasil, etaconazole, etaphos, etem, ethaboxam, ethachlor,ethalfluralin, ethametsulfuron, ethaprochlor, ethephon, ethidimuron,ethiofencarb, ethiolate, ethion, ethiozin, ethiprole, ethirimol,ethoate-methyl, ethobenzanid, ethofumesate, ethohexadiol, ethoprop,ethoprophos, ethoxyfen, ethoxyquin, ethoxysulfuron, ethychlozate, ethylformate, ethyl pyrophosphate, ethylan, ethyl-DDD, ethylene, ethylenedibromide, ethylene dichloride, ethylene oxide, ethylicin, ethylmercury2,3-dihydroxypropyl mercaptide, ethylmercury acetate, ethylmercurybromide, ethylmercury chloride, ethylmercury phosphate, etinofen, ETM,etnipromid, etobenzanid, etofenprox, etoxazole, etridiazole, etrimfos,étrimphos, eugenol, EXD, famoxadone, famphur, fenac, fenamidone,fenaminosulf, fenaminstrobin, fenamiphos, fenapanil, fenarimol,fenasulam, fenazaflor, fenazaquin, fenbuconazole, fenbutatin oxide,fenchlorazole, fenchlorphos, fenclofos, fenclorim, fenethacarb,fenfluthrin, fenfuram, fenhexamid, fenidin, fenitropan, fenitrothion,fénizon, fenjuntong, fenobucarb, fenolovo, fenoprop, fenothiocarb,fenoxacrim, fenoxanil, fenoxaprop, fenoxaprop-P, fenoxasulfone,fenoxycarb, fenpiclonil, fenpirithrin, fenpropathrin, fenpropidin,fenpropimorph, fenpyrazamine, fenpyroximate, fenquinotrione, fenridazon,fenson, fensulfothion, fenteracol, fenthiaprop, fenthion,fenthion-ethyl, fentiaprop, fentin, fentrazamide, fentrifanil, fenuron,fenuron-TCA, fenvalerate, ferbam, ferimzone, ferric phosphate, ferroussulfate, fipronil, flamprop, flamprop-M, flazasulfuron, flocoumafen,flometoquin, flonicamid, florasulam, florpyrauxifen, fluacrypyrim,fluazaindolizine, fluazifop, fluazifop-P, fluazinam, fluazolate,fluazuron, flubendiamide, flubenzimine, flubrocythrinate, flucarbazone,flucetosulfuron, fluchloralin, flucofuron, flucycloxuron, flucythrinate,fludioxonil, fluénéthyl, fluenetil, fluensulfone, flufenacet,flufenerim, flufenican, flufenoxuron, flufenoxystrobin, flufenprox,flufenpyr, flufenzine, flufiprole, fluhexafon, flumethrin, flumetover,flumetralin, flumetsulam, flumezin, flumiclorac, flumioxazin,flumipropyn, flumorph, fluometuron, fluopicolide, fluopyram,fluorbenside, fluoridamid, fluoroacetamide, fluoroacetic acid,fluorochloridone, fluorodifen, fluoroglycofen, fluoroimide, fluoromide,fluoromidine, fluoronitrofen, fluoroxypyr, fluothiuron, fluotrimazole,fluoxastrobin, flupoxam, flupropacil, flupropadine, flupropanate,flupyradifurone, flupyrsulfuron, fluquinconazole, fluralaner, flurazole,flurecol, flurenol, fluridone, flurochloridone, fluromidine, fluroxypyr,flurprimidol, flursulamid, flurtamone, flusilazole, flusulfamide,flutenzine, fluthiacet, fluthiamide, flutianil, flutolanil, flutriafol,fluvalinate, fluxametamide, fluxapyroxad, fluxofenim, folpel, folpet,fomesafen, fonofos, foramsulfuron, forchlorfenuron, formaldehyde,formetanate, formothion, formparanate, fosamine, fosetyl, fosmethilan,fospirate, fosthiazate, fosthietan, frontalin, fthalide, fuberidazole,fucaojing, fucaomi, fujunmanzhi, fulumi, fumarin, funaihecaoling,fuphenthiourea, furalane, furalaxyl, furamethrin, furametpyr, furantebufenozide, furathiocarb, furcarbanil, furconazole, furconazole-cis,furethrin, furfural, furilazole, furmecyclox, furophanate, furyloxyfen,gamma-BHC, gamma-cyhalothrin, gamma-HCH, genit, gibberellic acid,gibberellin A3, gibberellins, gliftor, glitor, glucochloralose,glufosinate, glufosinate-P, glyodin, glyoxime, glyphosate, glyphosine,gossyplure, grandlure, griseofulvin, guanoctine, guazatine, halacrinate,halauxifen, halfenprox, halofenozide, halosafen, halosulfuron,haloxydine, haloxyfop, haloxyfop-P, haloxyfop-R, HCA, HCB, HCH, hemel,hempa, HEOD, heptachlor, heptafluthrin, heptenophos, heptopargil,herbimycin, herbimycin A, heterophos, hexachlor, hexachloran,hexachloroacetone, hexachlorobenzene, hexachlorobutadiene,hexachlorophene, hexaconazole, hexaflumuron, hexafluoramin, hexaflurate,hexalure, hexamide, hexazinone, hexylthiofos, hexythiazox, HHDN,holosulf, homobrassinolide, huancaiwo, huanchongjing, huangcaoling,huanjunzuo, hydramethylnon, hydrargaphen, hydrated lime, hydrogencyanamide, hydrogen cyanide, hydroprene, hydroxyisoxazole, hymexazol,hyquincarb, IAA, IBA, IBP, icaridin, imazalil, imazamethabenz, imazamox,imazapic, imazapyr, imazaquin, imazethapyr, imazosulfuron,imibenconazole, imicyafos, imidacloprid, imidaclothiz, iminoctadine,imiprothrin, inabenfide, indanofan, indaziflam, indoxacarb, inezin,infusorial earth, iodobonil, iodocarb, iodofenphos, iodomethane,iodosulfuron, iofensulfuron, ioxynil, ipazine, IPC, ipconazole,ipfencarbazone, ipfentrifluconazole, iprobenfos, iprodione,iprovalicarb, iprymidam, ipsdienol, ipsenol, IPSP, IPX, isamidofos,isazofos, isobenzan, isocarbamid, isocarbamide, isocarbophos, isocil,isodrin, isofenphos, isofenphos-methyl, isofetamid, isolan,isomethiozin, isonoruron, isopamphos, isopolinate, isoprocarb,isoprocil, isopropalin, isopropazol, isoprothiolane, isoproturon,isopyrazam, isopyrimol, isothioate, isotianil, isouron, isovaledione,isoxaben, isoxachlortole, isoxadifen, isoxaflutole, isoxapyrifop,isoxathion, isuron, ivermectin, ixoxaben, izopamfos, izopamphos,japonilure, japothrins, jasmolin I, jasmolin II, jasmonic acid,jiahuangchongzong, jiajizengxiaolin, jiaxiangjunzhi, jiecaowan,jiecaoxi, Jinganmycin A, jodfenphos, juvenile hormone I, juvenilehormone II, juvenile hormone III, kadethrin, kappa-bifenthrin,kappa-tefluthrin, karbutilate, karetazan, kasugamycin, kejunlin,kelevan, ketospiradox, kieselguhr, kinetin, kinoprene, kiralaxyl,kresoxim-methyl, kuicaoxi, lactofen, lambda-cyhalothrin, lancotrione,latilure, lead arsenate, lenacil, lepimectin, leptophos, lianbenjingzhi,lime sulfur, lindane, lineatin, linuron, lirimfos, litlure, looplure,lufenuron, lüfuqingchongxianan, lüxiancaolin, lvdingjunzhi, lvfumijvzhi,lvxiancaolin, lythidathion, M-74, M-81, MAA, magnesium phosphide,malathion, maldison, maleic hydrazide, malonoben, maltodextrin, MAMA,mancopper, mancozeb, mandestrobin, mandipropamid, maneb, matrine,mazidox, MCC, MCP, MCPA, MCPA-thioethyl, MCPB, MCPP, mebenil, mecarbam,mecarbinzid, mecarphon, mecoprop, mecoprop-P, medimeform, medinoterb,medlure, mefenacet, mefenoxam, mefenpyr, mefentrifluconazole,mefluidide, megatomoic acid, melissyl alcohol, melitoxin, MEMC, menazon,MEP, mepanipyrim, meperfluthrin, mephenate, mephosfolan, mepiquat,mepronil, meptyldinocap, mercaptodimethur, mercaptophos, mercaptophosthiol, mercaptothion, mercuric chloride, mercuric oxide, mercurouschloride, merphos, merphos oxide, mesoprazine, mesosulfuron, mesotrione,mesulfen, mesulfenfos, mesulphen, metacresol, metaflumizone, metalaxyl,metalaxyl-M, metaldehyde, metam, metamifop, metamitron, metaphos,metaxon, metazachlor, metazosulfuron, metazoxolon, metconazole, metepa,metflurazon, methabenzthiazuron, methacrifos, methalpropalin, metham,methamidophos, methasulfocarb, methazole, methfuroxam, methibenzuron,methidathion, methiobencarb, methiocarb, methiopyrisulfuron, methiotepa,methiozolin, methiuron, methocrotophos, métholcarb, methometon,methomyl, methoprene, methoprotryn, methoprotryne, methoquin-butyl,methothrin, methoxychlor, methoxyfenozide, methoxyphenone, methylapholate, methyl bromide, methyl eugenol, methyl iodide, methylisothiocyanate, methyl parathion, methylacetophos, methylchloroform,methyldithiocarbamic acid, methyldymron, methylene chloride,methyl-isofenphos, methylmercaptophos, methylmercaptophos oxide,methylmercaptophos thiol, methylmercury benzoate, methylmercurydicyandiamide, methylmercury pentachlorophenoxide, methylneodecanamide,methylnitrophos, methyltriazothion, metiozolin, metiram, metiram-zinc,metobenzuron, metobromuron, metofluthrin, metolachlor, metolcarb,metometuron, metominostrobin, metosulam, metoxadiazone, metoxuron,metrafenone, metriam, metribuzin, metrifonate, metriphonate,metsulfovax, metsulfuron, mevinphos, mexacarbate, miechuwei, mieshuan,miewenjuzhi, milbemectin, milbemycin oxime, milneb, mimanan, mipafox,MIPC, mirex, MNAF, moguchun, molinate, molosultap, momfluorothrin,monalide, monisuron, monoamitraz, monochloroacetic acid, monocrotophos,monolinuron, monomehypo, monosulfiram, monosulfuron, monosultap,monuron, monuron-TCA, morfamquat, moroxydine, morphothion, morzid,moxidectin, MPMC, MSMA, MTMC, muscalure, myclobutanil, myclozolin,myricyl alcohol, N-(ethylmercury)-p-toluenesulphonanilide, NAA, NAAm,nabam, naftalofos, naled, naphthalene, naphthaleneacetamide, naphthalicanhydride, naphthalophos, naphthoxyacetic acids, naphthylacetic acids,naphthylindane-1,3-diones, naphthyloxyacetic acids, naproanilide,napropamide, napropamide-M, naptalam, natamycin, NBPOS, neburea,neburon, nendrin, neonicotine, nichlorfos, niclofen, niclosamide,nicobifen, nicosulfuron, nicotine, nicotine sulfate, nifluridide,nikkomycins, NIP, nipyraclofen, nipyralofen, nitenpyram, nithiazine,nitralin, nitrapyrin, nitrilacarb, nitrofen, nitrofluorfen,nitrostyrene, nitrothalisopropyl, nobormide, nonanol, norbormide, norea,norflurazon, nornicotine, noruron, novaluron, noviflumuron, NPA,nuarimol, nuranone, OCH, octachlorodipropyl ether, octhilinone,o-dichlorobenzene, ofurace, omethoate, o-phenylphenol, orbencarb,orfralure, orthobencarb, ortho-dichlorobenzene, orthosulfamuron,oryctalure, orysastrobin, oryzalin, osthol, osthole, ostramone, ovatron,ovex, oxabetrinil, oxadiargyl, oxadiazon, oxadixyl, oxamate, oxamyl,oxapyrazon, oxapyrazone, oxasulfuron, oxathiapiprolin, oxaziclomefone,oxine-copper, oxine-Cu, oxolinic acid, oxpoconazole, oxycarboxin,oxydemeton-methyl, oxydeprofos, oxydisulfoton, oxyenadenine,oxyfluorfen, oxymatrine, oxytetracycline, oxythioquinox, PAC,paclobutrazol, paichongding, palléthrine, PAP, para-dichlorobenzene,parafluron, paraquat, parathion, parathion-methyl, parinol, Paris green,PCNB, PCP, PCP-Na, p-dichlorobenzene, PDJ, pebulate, pédinex,pefurazoate, pelargonic acid, penconazole, pencycuron, pendimethalin,penfenate, penflufen, penfluron, penoxalin, penoxsulam,pentachlorophenol, pentachlorophenyl laurate, pentanochlor,penthiopyrad, pentmethrin, pentoxazone, perchlordecone, perfluidone,permethrin, pethoxamid, PHC, phenamacril, phenamacril-ethyl,phénaminosulf, phenazine oxide, phénétacarbe, phenisopham, phenkapton,phenmedipham, phenmedipham-ethyl, phenobenzuron, phenothiol, phenothrin,phenproxide, phenthoate, phenylmercuriurea, phenylmercury acetate,phenylmercury chloride, phenylmercury derivative of pyrocatechol,phenylmercury nitrate, phenylmercury salicylate, phorate, phosacetim,phosalone, phosametine, phosazetim, phosazetin, phoscyclotin,phosdiphen, phosethyl, phosfolan, phosfolanmethyl, phosglycin, phosmet,phosnichlor, phosphamide, phosphamidon, phosphine, phosphinothricin,phosphocarb, phosphorus, phostin, phoxim, phoxim-methyl, phthalide,phthalophos, phthalthrin, picarbutrazox, picaridin, picloram,picolinafen, picoxystrobin, pimaricin, pindone, pinoxaden, piperalin,piperazine, piperonyl butoxide, piperonyl cyclonene, piperophos,piproctanly, piproctanyl, piprotal, pirimetaphos, pirimicarb, piriminil,pirimioxyphos, pirimiphos-ethyl, pirimiphos-methyl, pival, pivaldione,plifenate, PMA, PMP, polybutenes, polycarbamate, polychlorcamphene,polyethoxyquinoline, polyoxin D, polyoxins, polyoxorim, polythialan,potassium arsenite, potassium azide, potassium cyanate, potassiumethylxanthate, potassium naphthenate, potassium polysulfide, potassiumthiocyanate, pp′-DDT, prallethrin, precocene I, precocene II, precoceneIII, pretilachlor, primidophos, primisulfuron, probenazole, prochloraz,proclonol, procyazine, procymidone, prodiamine, profenofos, profluazol,profluralin, profluthrin, profoxydim, profurite-aminium, proglinazine,prohexadione, prohydrojasmon, promacyl, promecarb, prometon, prometryn,prometryne, promurit, pronamide, propachlor, propafos, propamidine,propamocarb, propanil, propaphos, propaquizafop, propargite,proparthrin, propazine, propetamphos, propham, propiconazole, propidine,propineb, propisochlor, propoxur, propoxycarbazone, propyl isome,propyrisulfuron, propyzamide, proquinazid, prosuler, prosulfalin,prosulfocarb, prosulfuron, prothidathion, prothiocarb, prothioconazole,prothiofos, prothoate, protrifenbute, proxan, prymidophos, prynachlor,psoralen, psoralene, pydanon, pydiflumetofen, pyflubumide, pymetrozine,pyracarbolid, pyraclofos, pyraclonil, pyraclostrobin, pyraflufen,pyrafluprole, pyramat, pyrametostrobin, pyraoxystrobin, pyrasulfotole,pyraziflumid, pyrazolate, pyrazolynate, pyrazon, pyrazophos,pyrazosulfuron, pyrazothion, pyrazoxyfen, pyresmethrin, pyrethrin I,pyrethrin II, pyrethrins, pyribambenz-isopropyl, pyribambenz-propyl,pyribencarb, pyribenzoxim, pyributicarb, pyriclor, pyridaben, pyridafol,pyridalyl, pyridaphenthion, pyridaphenthione, pyridate, pyridinitril,pyrifenox, pyrifluquinazon, pyriftalid, pyrimétaphos, pyrimethanil,pyrimicarbe, pyrimidifen, pyriminobac, pyriminostrobin,pyrimiphos-éthyl, pyrimiphos-methyl, pyrimisulfan, pyrimitate,pyrinuron, pyriofenone, pyriprole, pyripropanol, pyriproxyfen,pyrisoxazole, pyrithiobac, pyrolan, pyroquilon, pyroxasulfone,pyroxsulam, pyroxychlor, pyroxyfur, qincaosuan, qingkuling, quassia,quinacetol, quinalphos, quinalphos-methyl, quinazamid, quinclorac,quinconazole, quinmerac, quinoclamine, quinofumelin, quinomethionate,quinonamid, quinothion, quinoxyfen, quintiofos, quintozene, quizalofop,quizalofop-P, quwenzhi, quyingding, rabenzazole, rafoxanide,R-diniconazole, rebemide, reglone, renriduron, rescalure, resmethrin,rhodethanil, rhodojaponin-III, ribavirin, rimsulfuron, rizazole,R-metalaxyl, rodéthanil, ronnel, rotenone, ryania, sabadilla,saflufenacil, saijunmao, saisentong, salicylanilide, salifluofen,sanguinarine, santonin, S-bioallethrin, schradan, scilliroside,sebuthylazine, secbumeton, sedaxane, selamectin, semiamitraz, sesamex,sesamolin, sesone, sethoxydim, sevin, shuangjiaancaolin,shuangjianancaolin, S-hydroprene, siduron, sifumijvzhi, siglure,silafluofen, silatrane, silica aerogel, silica gel, silthiofam,silthiopham, silthiophan, silvex, simazine, simeconazole, simeton,simetryn, simetryne, sintofen, S-kinoprene, slaked lime, SMA,S-methoprene, S-metolachlor, sodium arsenite, sodium azide, sodiumchlorate, sodium cyanide, sodium fluoride, sodium fluoroacetate, sodiumhexafluorosilicate, sodium naphthenate, sodium o-phenylphenoxide, sodiumorthophenylphenoxide, sodium pentachlorophenate, sodiumpentachlorophenoxide, sodium polysulfide, sodium silicofluoride, sodiumtetrathiocarbonate, sodium thiocyanate, solan, sophamide, spinetoram,spinosad, spirodiclofen, spiromesifen, spirotetramat, spiroxamine,stirofos, streptomycin, strychnine, sulcatol, sulcofuron, sulcotrione,sulfallate, sulfentrazone, sulfiram, sulfluramid, sulfodiazole,sulfometuron, sulfosate, sulfosulfuron, sulfotep, sulfotepp,sulfoxaflor, sulfoxide, sulfoxime, sulfur, sulfuric acid, sulfurylfluoride, sulglycapin, sulphosate, sulprofos, sultropen, swep,tau-fluvalinate, tavron, tazimcarb, TBTO, TBZ, TCA, TCBA, TCMTB, TCNB,TDE, tebuconazole, tebufenozide, tebufenpyrad, tebufloquin,tebupirimfos, tebutam, tebuthiuron, tecloftalam, tecnazene, tecoram,tedion, teflubenzuron, tefluthrin, tefuryltrione, tembotrione, temefos,temephos, tepa, TEPP, tepraloxydim, teproloxydim, terallethrin,terbacil, terbucarb, terbuchlor, terbufos, terbumeton, terbuthylazine,terbutol, terbutryn, terbutryne, terraclor, terramicin, terramycin,tetcyclacis, tetrachloroethane, tetrachlorvinphos, tetraconazole,tetradifon, tetradisul, tetrafluron, tetramethrin, tetramethylfluthrin,tetramine, tetranactin, tetraniliprole, tetrapion, tetrasul, thalliumsulfate, thallous sulfate, thenylchlor, theta-cypermethrin,thiabendazole, thiacloprid, thiadiazine, thiadifluor, thiamethoxam,thiameturon, thiapronil, thiazafluron, thiazfluron, thiazone, thiazopyr,thicrofos, thicyofen, thidiazimin, thidiazuron, thiencarbazone,thifensulfuron, thifluzamide, thimerosal, thimet, thiobencarb,thiocarboxime, thiochlorfenphim, thiochlorphenphime,thiocyanatodinitrobenzenes, thiocyclam, thiodan, thiodiazole-copper,thiodicarb, thiofanocarb, thiofanox, thiofluoximate, thiohempa,thiomersal, thiometon, thionazin, thiophanate, thiophanate-ethyl,thiophanate-methyl, thiophos, thioquinox, thiosemicarbazide, thiosultap,thiotepa, thioxamyl, thiram, thiuram, thuringiensin, tiabendazole,tiadinil, tiafenacil, tiaojiean, TIBA, tifatol, tiocarbazil, tioclorim,tioxazafen, tioxymid, tirpate, TMTD, tolclofos-methyl, tolfenpyrad,tolprocarb, tolpyralate, tolyfluanid, tolylfluanid, tolylmercuryacetate, tomarin, topramezone, toxaphene, TPN, tralkoxydim,tralocythrin, tralomethrin, tralopyril, transfluthrin, transpermethrin,tretamine, triacontanol, triadimefon, triadimenol, triafamone,triallate, tri-allate, triamiphos, triapenthenol, triarathene,triarimol, triasulfuron, triazamate, triazbutil, triaziflam, triazophos,triazothion, triazoxide, tribasic copper chloride, tribasic coppersulfate, tribenuron, tribufos, tributyltin oxide, tricamba, trichlamide,trichlopyr, trichlorfon, trichlormetaphos-3, trichloronat,trichloronate, trichlorotrinitrobenzenes, trichlorphon, triclopyr,triclopyricarb, tricresol, tricyclazole, tricyclohexyltin hydroxide,tridemorph, tridiphane, trietazine, trifenmorph, trifenofos,trifloxystrobin, trifloxysulfuron, trifludimoxazin, triflumezopyrim,triflumizole, triflumuron, trifluralin, triflusulfuron, trifop,trifopsime, triforine, trihydroxytriazine, trimedlure, trimethacarb,trimeturon, trinexapac, triphenyltin, triprene, tripropindan,triptolide, tritac, trithialan, triticonazole, tritosulfuron,trunc-call, tuoyelin, uniconazole, uniconazole-P, urbacide, uredepa,valerate, validamycin, validamycin A, valifenalate, valone, vamidothion,vangard, vaniliprole, vernolate, vinclozolin, vitamin D3, warfarin,xiaochongliulin, xinjunan, xiwojunan, xiwojunzhi, XMC, xylachlor,xylenols, xylylcarb, xymiazole, yishijing, zarilamid, zeatin,zengxiaoan, zengxiaolin, zeta-cypermethrin, zinc naphthenate, zincphosphide, zinc thiazole, zinc thiozole, zinc trichlorophenate, zinctrichlorophenoxide, zineb, ziram, zolaprofos, zoocoumarin, zoxamide,zuoanjunzhi, zuocaoan, zuojunzhi, zuomihuanglong, α-chlorohydrin,α-ecdysone, α-multistriatin, α-naphthaleneacetic acids, and β-ecdysone;

(2) the following molecules

-   -   (a)        N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-N-ethyl-3-((3,3,3-trifluoropropyl)thio)propanamide        (hereafter “AI-1”)

-   -   (b) a molecule known as Lotilaner that has the following        structure

and

-   -   (c) the following molecules in Table A

TABLE A Structure of M#-active ingredients M# Structure M1

M2

M3

M4

M5

M6

As used in this disclosure, each of the above is an active ingredient.For more information consult the “Compendium of Pesticide Common Names”located at Alanwood.net and various editions, including the on-lineedition, of “The Pesticide Manual” located at bcpcdata.com.

A particularly preferred selection of active ingredients are1,3-dichloropropene, chlorpyrifos, hexaflumuron, methoxyfenozide,noviflumuron, spinetoram, spinosad, and sulfoxaflor (hereafter“AIGA-2”).

Additionally, another particularly preferred selection of activeingredients are acequinocyl, acetamiprid, acetoprole, avermectin,azinphos-methyl, bifenazate, bifenthrin, carbaryl, carbofuran,chlorfenapyr, chlorfluazuron, chromafenozide, clothianidin, cyfluthrin,cypermethrin, deltamethrin, diafenthiuron, emamectin benzoate,endosulfan, esfenvalerate, ethiprole, etoxazole, fipronil, flonicamid,fluacrypyrim, gamma-cyhalothrin, halofenozide, indoxacarb,lambda-cyhalothrin, lufenuron, malathion, methomyl, novaluron,permethrin, pyridalyl, pyrimidifen, spirodiclofen, tebufenozide,thiacloprid, thiamethoxam, thiodicarb, tolfenpyrad, andzeta-cypermethrin (hereafter “AIGA-3”).

The term “alkenyl” means an acyclic, unsaturated (at least onecarbon-carbon double bond), branched or unbranched, substituentconsisting of carbon and hydrogen, for example, vinyl, allyl, butenyl,pentenyl, and hexenyl.

The term “alkenyloxy” means an alkenyl further consisting of acarbon-oxygen single bond, for example, allyloxy, butenyloxy,pentenyloxy, hexenyloxy.

The term “alkoxy” means an alkyl further consisting of a carbon-oxygensingle bond, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy,isobutoxy, and tert-butoxy.

The term “alkyl” means an acyclic, saturated, branched or unbranched,substituent consisting of carbon and hydrogen, for example, methyl,ethyl, propyl, isopropyl, butyl, and tert-butyl.

The term “alkynyl” means an acyclic, unsaturated (at least onecarbon-carbon triple bond), branched or unbranched, substituentconsisting of carbon and hydrogen, for example, ethynyl, propargyl,butynyl, and pentynyl.

The term “alkynyloxy” means an alkynyl further consisting of acarbon-oxygen single bond, for example, pentynyloxy, hexynyloxy,heptynyloxy, and octynyloxy.

The term “aryl” means a cyclic, aromatic substituent consisting ofhydrogen and carbon, for example, phenyl, naphthyl, and biphenyl.

The term “biopesticide” means a microbial biological pest control agentthat, in general, is applied in a similar manner to chemical pesticides.Commonly they are bacterial, but there are also examples of fungalcontrol agents, including Trichoderma spp. and Ampelomyces quisqualis.One well-known biopesticide example is Bacillus species, a bacterialdisease of Lepidoptera, Coleoptera, and Diptera. Biopesticides includeproducts based on entomopathogenic fungi (e.g. Metarhizium anisopliae),entomopathogenic nematodes (e.g. Steinernema feltiae), andentomopathogenic viruses (e.g. Cydia pomonella granulovirus). Otherexamples of entomopathogenic organisms include, but are not limited to,baculoviruses, protozoa, and Microsporidia. For the avoidance of doubt,biopesticides are active ingredients.

The term “cycloalkenyl” means a monocyclic or polycyclic, unsaturated(at least one carbon-carbon double bond) substituent consisting ofcarbon and hydrogen, for example, cyclobutenyl, cyclopentenyl,cyclohexenyl, norbornenyl, bicyclo[2.2.2]octenyl, tetrahydronaphthyl,hexahydronaphthyl, and octahydronaphthyl.

The term “cycloalkenyloxy” means a cycloalkenyl further consisting of acarbon-oxygen single bond, for example, cyclobutenyloxy,cyclopentenyloxy, norbornenyloxy, and bicyclo[2.2.2]octenyloxy.

The term “cycloalkyl” means a monocyclic or polycyclic, saturatedsubstituent consisting of carbon and hydrogen, for example, cyclopropyl,cyclobutyl, cyclopentyl, norbornyl, bicyclo[2.2.2]octyl, anddecahydronaphthyl.

The term “cycloalkoxy” means a cycloalkyl further consisting of acarbon-oxygen single bond, for example, cyclopropyloxy, cyclobutyloxy,cyclopentyloxy, norbornyloxy, and bicyclo[2.2.2]octyloxy.

The term “halo” means fluoro, chloro, bromo, and iodo.

The term “haloalkoxy” means an alkoxy further consisting of, from one tothe maximum possible number of identical or different, halos, forexample, fluoromethoxy, trifluoromethoxy, 2,2-difluoropropoxy,chloromethoxy, trichloromethoxy, 1,1,2,2-tetrafluoroethoxy, andpentafluoroethoxy.

The term “haloalkyl” means an alkyl further consisting of, from one tothe maximum possible number of, identical or different, halos, forexample, fluoromethyl, trifluoromethyl, 2,2-difluoropropyl,chloromethyl, trichloromethyl, and 1,1,2,2-tetrafluoroethyl.

The term “heterocyclyl” means a cyclic substituent that may be aromatic,fully saturated, or partially or fully unsaturated, where the cyclicstructure contains at least one carbon and at least one heteroatom,where said heteroatom is nitrogen, sulfur, or oxygen. Examples are:

(1) aromatic heterocyclyl substituents include, but are not limited to,benzofuranyl, benzoisothiazolyl, benzoisoxazolyl, benzothienyl,benzothiazolyl, benzoxazolyl, cinnolinyl, furanyl, imidazolyl,indazolyl, indolyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl,oxadiazolyl, oxazolinyl, oxazolyl, phthalazinyl, pyrazinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl,quinolinyl, quinoxalinyl, tetrazolyl, thiazolinyl, thiazolyl, thienyl,triazinyl, and triazolyl;

(2) fully saturated heterocyclyl substituents include, but are notlimited to, piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl,tetrahydrofuranyl, and tetrahydropyranyl;

(3) partially or fully unsaturated heterocyclyl substituents include,but are not limited to, 4,5-dihydro-isoxazolyl, 4,5-dihydro-oxazolyl,4,5-dihydro-1H-pyrazolyl, 2,3-dihydro-[1,3,4]-oxadiazolyl, and1,2,3,4-tetrahydro-quinolinyl; and

(4) Additional examples of heterocyclyls include the following:

The term “locus” means a habitat, breeding ground, plant, seed, soil,material, or environment, in which a pest is growing, may grow, or maytraverse. For example, a locus may be: where crops, trees, fruits,cereals, fodder species, vines, turf, and/or ornamental plants, aregrowing; where domesticated animals are residing; the interior orexterior surfaces of buildings (such as places where grains are stored);the materials of construction used in buildings (such as impregnatedwood); and the soil around buildings.

The phrase “MoA Material” means an active ingredient having a mode ofaction (“MoA”) as indicated in IRAC MoA Classification v. 7.4, locatedat irac-online.org., which describes the following groups.

(1) Acetylcholinesterase (AChE) inhibitors, includes the followingactive ingredients acephate, alanycarb, aldicarb, azamethiphos,azinphos-ethyl, azinphos-methyl, bendiocarb, benfuracarb, butocarboxim,butoxycarboxim, cadusafos, carbaryl, carbofuran, carbosulfan,chlorethoxyfos, chlorfenvinphos, chlormephos, chlorpyrifos,chlorpyrifos-methyl, coumaphos, cyanophos, demeton-S-methyl, diazinon,dichlorvos/DDVP, dicrotophos, dimethoate, dimethylvinphos, disulfoton,EPN, ethiofencarb, ethion, ethoprophos, famphur, fenamiphos,fenitrothion, fenobucarb, fenthion, formetanate, fosthiazate,furathiocarb, heptenophos, imicyafos, isofenphos, isoprocarb, isopropylO-(methoxyaminothio-phosphoryl)salicylate, isoxathion, malathion,mecarbam, methamidophos, methidathion, methiocarb, methomyl, metolcarb,mevinphos, monocrotophos, Naled, omethoate, oxamyl, oxydemeton-methyl,parathion, parathion-methyl, phenthoate, phorate, phosalone, phosmet,phosphamidon, phoxim, pirimicarb, pirimiphos-methyl, profenofos,propetamphos, propoxur, prothiofos, pyraclofos, pyridaphenthion,quinalphos, sulfotep, tebupirimfos, temephos, terbufos,tetrachlorvinphos, thiodicarb, thiofanox, thiometon, triazamate,triazophos, trichlorfon, trimethacarb, vamidothion, XMC, and xylylcarb.

(2) GABA-gated chloride channel antagonists, includes the followingactive ingredients chlordane, endosulfan, ethiprole, and fipronil.

(3) Sodium channel modulators, includes the following active ingredientsacrinathrin, allethrin, d-cis-trans allethrin, d-trans allethrin,bifenthrin, bioallethrin, bioallethrin S-cyclopentenyl, bioresmethrin,cycloprothrin, cyfluthrin, beta-cyfluthrin, cyhalothrin,lambda-cyhalothrin, gamma-cyhalothrin, cypermethrin, alpha-cypermethrin,beta-cypermethrin, theta-cypermethrin, zeta-cypermethrin, cyphenothrin[(1R)-trans-isomers], deltamethrin, empenthrin [(EZ)-(1R)-isomers],esfenvalerate, etofenprox, fenpropathrin, fenvalerate, flucythrinate,flumethrin, tau-fluvalinate, halfenprox, imiprothrin, kadethrin,permethrin, phenothrin [(1R)-trans-isomer], prallethrin, pyrethrins(pyrethrum), resmethrin, silafluofen, tefluthrin, tetramethrin,tetramethrin [(1R)-isomers], tralomethrin, and transfluthrin, andmethoxychlor.

(4) Nicotinic acetylcholine receptor (nAChR) agonists, includes thefollowing active ingredients

-   -   (4A) acetamiprid, clothianidin, dinotefuran, imidacloprid,        nitenpyram, thiacloprid, thiamethoxam,    -   (4B) nicotine,    -   (4C) sulfoxaflor,    -   (4D) flupyradifurone,    -   (4E) triflumezopyrim and dicloromezotiaz.

(5) Nicotinic acetylcholine receptor (nAChR) allosteric activators,includes the following active ingredients spinetoram and spinosad.

(6) Chloride channel activators, includes the following activeingredients abamectin, emamectin benzoate, lepimectin, and milbemectin.

(7) Juvenile hormone mimics, includes the following active ingredientshydroprene, kinoprene, methoprene, fenoxycarb, and pyriproxyfen.

(8) Miscellaneous nonspecific (multi-site) inhibitors, includes thefollowing active ingredients methyl bromide, chloropicrin, sulfurylfluoride, borax, boric acid, disodium octaborate, sodium borate, sodiummetaborate, tartar emetic, diazomet, and metam.

(9) Modulators of Chordotonal Organs, includes the following activeingredients pymetrozine and flonicamid.

(10) Mite growth inhibitors, includes the following active ingredientsclofentezine, hexythiazox, diflovidazin, and etoxazole.

(11) Microbial disruptors of insect midgut membranes, includes thefollowing active ingredients Bacillus thuringiensis subsp. israelensis,Bacillus thuringiensis subsp. aizawai, Bacillus thuringiensis subsp.kurstaki, Bacillus thuringiensis subsp. tenebrionenis, Bt crop proteins(Cry1Ab, Cry1Ac, Cry1Fa, Cry1A.105, Cry2Ab, Vip3A, mCry3A, Cry3Ab,Cry3Bb, Cry34Ab1/Cry35Ab1), and Bacillus sphaericus.

(12) Inhibitors of mitochondrial ATP synthase, includes the followingactive ingredients tetradifon, propargite, azocyclotin, cyhexatin,fenbutatin oxide, and diafenthiuron.

(13) Uncouplers of oxidative phosphorylation via disruption of theproton gradient, includes the following active ingredients chlorfenapyr,DNOC, and sulfluramid.

(14) Nicotinic acetylcholine receptor (nAChR) channel blockers, includesthe following active ingredients bensultap, cartap hydrochloride,thiocyclam, and thiosultap-sodium.

(15) Inhibitors of chitin biosynthesis, type 0, includes the followingactive ingredients bistrifluron, chlorfluazuron, diflubenzuron,flucycloxuron, flufenoxuron, hexaflumuron, lufenuron, novaluron,noviflumuron, teflubenzuron, and triflumuron.

(16) Inhibitors of chitin biosynthesis, type 1, includes the followingactive ingredient buprofezin. (17) Moulting disruptor, Dipteran,includes the following active ingredient cyromazine.

(18) Ecdysone receptor agonists, includes the following activeingredients chromafenozide, halofenozide, methoxyfenozide, andtebufenozide.

(19) Octopamine receptor agonists, includes the following activeingredient amitraz.

(20) Mitochondrial complex III electron transport inhibitors, includesthe following active ingredients hydramethylnon, acequinocyl, andfluacrypyrim.

(21) Mitochondrial complex I electron transport inhibitors, includes thefollowing active ingredients fenazaquin, fenpyroximate, pyrimidifen,pyridaben, tebufenpyrad, tolfenpyrad, and rotenone.

(22) Voltage-dependent sodium channel blockers, includes the followingactive ingredients indoxacarb and metaflumizone.

(23) Inhibitors of acetyl CoA carboxylase, includes the following activeingredients spirodiclofen, spiromesifen, and spirotetramat.

(24) Mitochondrial complex IV electron transport inhibitors, includesthe following active ingredients, aluminium phosphide, calciumphosphide, phosphine, zinc phosphide, and cyanide.

(25) Mitochondrial complex II electron transport inhibitors, includesthe following active ingredients cyenopyrafen, cyflumetofen, andpyflubumide, and

(28) Ryanodine receptor modulators, includes the following activeingredients chlorantraniliprole, cyantraniliprole, and flubendiamide.

Groups 26 and 27 are unassigned in this version of the classificationscheme. Additionally, there is a Group UN that contains activeingredients of unknown or uncertain mode of action. This group includesthe following active ingredients, azadirachtin, benzoximate, bifenazate,bromopropylate, chinomethionat, cryolite, dicofol, pyridalyl, andpyrifluquinazon.

The term “pest” means an organism that is detrimental to humans, orhuman concerns (such as, crops, food, livestock, etc.), where saidorganism is from Phyla Arthropoda, Mollusca, or Nematoda. Particularexamples are ants, aphids, bed bugs, beetles, bristletails,caterpillars, cockroaches, crickets, earwigs, fleas, flies,grasshoppers, grubs, hornets, jassids, leafhoppers, lice, locusts,maggots, mealybugs, mites, moths, nematodes, plantbugs, planthoppers,psyllids, sawflies, scales, silverfish, slugs, snails, spiders,springtails, stink bugs, symphylans, termites, thrips, ticks, wasps,whiteflies, and wireworms.

Additional examples are pests in

(1) Subphyla Chelicerata, Myriapoda, and Hexapoda.

(2) Classes of Arachnida, Symphyla, and Insecta.

(3) Order Anoplura. A non-exhaustive list of particular genera includes,but is not limited to, Haematopinus spp., Hoplopleura spp., Linognathusspp., Pediculus spp., Polyplax spp., Solenopotes spp., andNeohaematopinis spp. A non-exhaustive list of particular speciesincludes, but is not limited to, Haematopinus asini, Haematopinus suis,Linognathus setosus, Linognathus ovillus, Pediculus humanus capitis,Pediculus humanus humanus, and Pthirus pubis.

(4) Order Coleoptera. A non-exhaustive list of particular generaincludes, but is not limited to, Acanthoscelides spp., Agriotes spp.,Anthonomus spp., Apion spp., Apogonia spp., Araecerus spp., Aulacophoraspp., Bruchus spp., Cerosterna spp., Cerotoma spp., Ceutorhynchus spp.,Chaetocnema spp., Colaspis spp., Ctenicera spp., Curculio spp.,Cyclocephala spp., Diabrotica spp., Dinoderus spp., Gnathocerus spp.,Hemicoelus spp., Heterobostruchus spp., Hypera spp., Ips spp., Lyctusspp., Megascelis spp., Meligethes spp., Mezium spp., Niptus spp.,Otiorhynchus spp., Pantomorus spp., Phyllophaga spp., Phyllotreta spp.,Ptinus spp., Rhizotrogus spp., Rhynchites spp., Rhynchophorus spp.,Scolytus spp., Sphenophorus spp., Sitophilus spp., Tenebrio spp., andTribolium spp. A non-exhaustive list of particular species includes, butis not limited to, Acanthoscelides obtectus, Agrilus planipennis,Ahasverus advena, Alphitobius diaperinus, Anoplophora glabripennis,Anthonomus grandis, Anthrenus verbasci, Anthrenus falvipes, Ataeniusspretulus, Atomaria linearis, Attagenus unicolor, Bothynoderespunctiventris, Bruchus pisorum, Callosobruchus maculatus, Carpophilushemipterus, Cassida vittata, Cathartus quadricollis, Cerotomatrifurcata, Ceutorhynchus assimilis, Ceutorhynchus napi, Conoderusscalaris, Conoderus stigmosus, Conotrachelus nenuphar, Cotinis nitida,Crioceris asparagi, Cryptolestes ferrugineus, Cryptolestes pusillus,Cryptolestes turcicus, Cylindrocopturus adspersus, Deporaus marginatus,Dermestes lardarius, Dermestes maculatus, Epilachna varivestis,Euvrilletta peltata, Faustinus cubae, Hylobius pales, Hylotrupesbajulus, Hypera postica, Hypothenemus hampei, Lasioderma serricome,Leptinotarsa decemlineata, Limonius canus, Liogenys fuscus, Liogenyssuturalis, Lissorhoptrus oryzophilus, Lophocateres pusillus, Lyctusplanicollis, Maecolaspis joliveti, Melanotus communis, Meligethesaeneus, Melolontha melolontha, Necrobia rufipes, Oberea brevis, Oberealinearis, Oryctes rhinoceros, Oryzaephilus mercator, Oryzaephilussurinamensis, Oulema melanopus, Oulema oryzae, Phyllophaga cuyabana,Polycaon stoutti, Popillia japonica, Prostephanus truncatus, Rhyzoperthadominica, Sitona lineatus, Sitophilus granarius, Sitophilus oryzae,Sitophilus zeamais, Stegobium paniceum, Tenebroides mauritanicus,Tribolium castaneum, Tribolium confusum, Trogoderma granarium,Trogoderma variabile, Xestobium rufovillosum, and Zabrus tenebrioides.

(5) Order Dermaptera. A non-exhaustive list of particular speciesincludes, but is not limited to, Forficula auricularia.

(6) Order Blattaria. A non-exhaustive list of particular speciesincludes, but is not limited to, Blattella germanica, Blattellaasahinai, Blatta orientalis, Blatta lateralis, Parcoblattapennsylvanica, Periplaneta americana, Periplaneta australasiae,Periplaneta brunnea, Periplaneta fuliginosa, Pycnoscelus surinamensis,and Supella longipalpa.

(7) Order Diptera. A non-exhaustive list of particular genera includes,but is not limited to, Aedes spp., Agromyza spp., Anastrepha spp.,Anopheles spp., Bactrocera spp., Ceratitis spp., Chrysops spp.,Cochliomyia spp., Contarinia spp., Culex spp., Culicoides spp.,Dasineura spp., Delia spp., Drosophila spp., Fannia spp., Hylemya spp.,Liriomyza spp., Musca spp., Phorbia spp., Pollenia spp., Psychoda spp.,Simulium spp., Tabanus spp., and Tipula spp. A non-exhaustive list ofparticular species includes, but is not limited to, Agromyza frontella,Anastrepha suspensa, Anastrepha ludens, Anastrepha obliqua, Bactroceracucurbitae, Bactrocera dorsalis, Bactrocera invadens, Bactrocera zonata,Ceratitis capitata, Dasineura brassicae, Delia platura, Fanniacanicularis, Fannia scalaris, Gasterophilus intestinalis, Gracilliaperseae, Haematobia irritans, Hypoderma lineatum, Liriomyza brassicae,Liriomyza sativa, Melophagus ovinus, Musca autumnalis, Musca domestica,Oestrus ovis, Oscinella frit, Pegomya betae, Piophila casei, Psilarosae, Rhagoletis cerasi, Rhagoletis pomonella, Rhagoletis mendax,Sitodiplosis mosellana, and Stomoxys calcitrans.

(8) Order Hemiptera. A non-exhaustive list of particular generaincludes, but is not limited to, Adelges spp., Aulacaspis spp.,Aphrophora spp., Aphis spp., Bemisia spp., Ceroplastes spp., Chionaspisspp., Chrysomphalus spp., Coccus spp., Empoasca spp., Euschistus spp.,Lepidosaphes spp., Lagynotomus spp., Lygus spp., Macrosiphum spp.,Nephotettix spp., Nezara spp., Nilaparvata spp., Philaenus spp.,Phytocoris spp., Piezodorus spp., Planococcus spp., Pseudococcus spp.,Rhopalosiphum spp., Saissetia spp., Therioaphis spp., Toumeyella spp.,Toxoptera spp., Trialeurodes spp., Triatoma spp., and Unaspis spp. Anon-exhaustive list of particular species includes, but is not limitedto, Acrostemum hilare, Acyrthosiphon pisum, Aleyrodes proletella,Aleurodicus dispersus, Aleurothrixus floccosus, Amrasca biguttulabiguttula, Aonidiella aurantii, Aphis fabae, Aphis gossypii, Aphisglycines, Aphis porni, Aulacorthum solani, Bactericera cockerelli,Bagrada hilaris, Bemisia argentifolii, Bemisia tabaci, Blissusleucopterus, Boisea trivittata, Brachycorynella asparagi, Brevenniarehi, Brevicoryne brassicae, Cacopsylla pyri, Cacopsylla pyricola,Calocoris norvegicus, Ceroplastes rubens, Cimex hemipterus, Cimexlectularius, Coccus pseudomagnoliarum, Dagbertus fasciatus, Dichelopsfurcatus, Diuraphis noxia, Diaphorina citri, Dysaphis plantaginea,Dysdercus suturellus, Edessa meditabunda, Empoasca vitis, Eriosomalanigerum, Erythroneura elegantula, Eurygaster maura, Euschistusconspersus, Euschistus heros, Euschistus servus, Halyomorpha halys,Helopeltis antonii, Hyalopterus pruni, Helopeltis antonii, Helopeltistheivora, Icerya purchasi, Idioscopus nitidulus, Jacobiasca formosana,Laodelphax striatellus, Lecanium corni, Leptocorisa oratorius,Leptocorisa varicornis, Lygus hesperus, Maconellicoccus hirsutus,Macrosiphum euphorbiae, Macrosiphum granarium, Macrosiphum rosae,Macrosteles quadrilineatus, Mahanarva frimbiolata, Megacopta cribraria,Metopolophium dirhodum, Mictis longicomis, Myzus persicae, Nasonoviaribisnigri, Nephotettix cincticeps, Neurocolpus longirostris, Nezaraviridula, Nilaparvata lugens, Paracoccus marginatus, Paratriozacockerelli, Parlatoria pergandii, Parlatoria ziziphi, Peregrinus maidis,Phylloxera vitifoliae, Physokermes piceae, Phytocoris califomicus,Phytocoris relativus, Piezodorus guildinii, Planococcus citri,Planococcus ficus, Poecilocapsus lineatus, Psallus vaccinicola,Pseudacysta perseae, Pseudococcus brevipes, Quadraspidiotus pemiciosus,Rhopalosiphum maidis, Rhopalosiphum padi, Saissetia oleae, Scaptocoriscastanea, Schizaphis graminum, Sitobion avenae, Sogatella furcifera,Trialeurodes vaporariorum, Trialeurodes abutiloneus, Unaspis yanonensis,and Zulia entrerriana.

(9) Order Hymenoptera. A non-exhaustive list of particular generaincludes, but is not limited to, Acromyrmex spp., Atta spp., Camponotusspp., Diprion spp., Dolichovespula spp., Formica spp., Monomorium spp.,Neodiprion spp., Paratrechina spp., Pheidole spp., Pogonomyrmex spp.,Polistes spp., Solenopsis spp., Technomyrmex, spp., Tetramorium spp.,Vespula spp., Vespa spp., and Xylocopa spp. A non-exhaustive list ofparticular species includes, but is not limited to, Athalia rosae, Attatexana, Caliroa cerasi, Cimbex americana, Iridomyrmex humilis,Linepithema humile, Mellifera Scutellata, Monomorium minimum, Monomoriumpharaonis, Neodiprion sertifer, Solenopsis invicta, Solenopsis geminata,Solenopsis molesta, Solenopsis richtery, Solenopsis xyloni, Tapinomasessile, and Wasmannia auropunctata.

(10) Order Isoptera. A non-exhaustive list of particular generaincludes, but is not limited to, Coptotermes spp., Cornitermes spp.,Cryptotermes spp., Heterotermes spp., Kalotermes spp., Incisitermesspp., Macrotermes spp., Marginitermes spp., Microcerotermes spp.,Procornitermes spp., Reticulitermes spp., Schedorhinotermes spp., andZootermopsis spp. A non-exhaustive list of particular species includes,but is not limited to, Coptotermes acinaciformis, Coptotermescurvignathus, Coptotermes frenchi, Coptotermes formosanus, Coptotermesgestroi, Cryptotermes brevis, Heterotermes aureus, Heterotermes tenuis,Incisitermes minor, Incisitermes snyderi, Microtermes obesi,Nasutitermes corniger, Odontotermes formosanus, Odontotermes obesus,Reticulitermes banyulensis, Reticulitermes grassei, Reticulitermesflavipes, Reticulitermes hageni, Reticulitermes hesperus, Reticulitermessantonensis, Reticulitermes speratus, Reticulitermes tibialis, andReticulitermes virginicus.

(11) Order Lepidoptera. A non-exhaustive list of particular generaincludes, but is not limited to, Adoxophyes spp., Agrotis spp.,Argyrotaenia spp., Cacoecia spp., Caloptilia spp., Chilo spp.,Chrysodeixis spp., Colias spp., Crambus spp., Diaphania spp., Diatraeaspp., Earias spp., Ephestia spp., Epimecis spp., Feltia spp., Gortynaspp., Helicoverpa spp., Heliothis spp., Indarbela spp., Lithocolletisspp., Loxagrotis spp., Malacosoma spp., Nemapogon spp., Peridroma spp.,Phyllonorycter spp., Pseudaletia spp., Plutella spp., Sesamia spp.,Spodoptera spp., Synanthedon spp., and Yponomeuta spp. A non-exhaustivelist of particular species includes, but is not limited to, Achaeajanata, Adoxophyes orana, Agrotis ipsilon, Alabama argillacea, Amorbiacuneana, Amyelois transitella, Anacamptodes defectaria, Anarsialineatella, Anomis sabulifera, Anticarsia gemmatalis, Archipsargyrospila, Archips rosana, Argyrotaenia citrana, Autographa gamma,Bonagota cranaodes, Borbo cinnara, Bucculatrix thurberiella, Capuareticulana, Carposina niponensis, Chlumetia trans versa, Choristoneurarosaceana, Cnaphalocrocis medinalis, Conopomorpha cramerella, Corcyracephalonica, Cossus cossus, Cydia caryana, Cydia funebrana, Cydiamolesta, Cydia nigricana, Cydia pomonella, Darna diducta, Diaphanianitidalis, Diatraea saccharalis, Diatraea grandiosella, Earias insulana,Earias vittella, Ecdytolopha aurantianum, Elasmopalpus lignosellus,Ephestia cautella, Ephestia elutella, Ephestia kuehniella, Epinotiaaporema, Epiphyas postvittana, Erionota thrax, Estigmene acrea,Eupoecilia ambiguella, Euxoa auxiliaris, Galleria mellonella, Grapholitamolesta, Hedylepta indicata, Helicoverpa armigera, Helicoverpa zea,Heliothis virescens, Hellula undalis, Keiferia lycopersicella,Leucinodes orbonalis, Leucoptera coffeella, Leucoptera malifoliella,Lobesia botrana, Loxagrotis albicosta, Lymantria dispar, Lyonetiaderkella, Mahasena corbetti, Mamestra brassicae, Manduca sexta, Marucatestulalis, Metisa plana, Mythimna unipuncta, Neoleucinodes elegantalis,Nymphula depunctalis, Operophtera brumata, Ostrinia nubilalis, Oxydiavesulia, Pandemis cerasana, Pandemis heparana, Papilio demodocus,Pectinophora gossypiella, Peridroma saucia, Perileucoptera coffeella,Phthorimaea operculella, Phyllocnistis citrella, Phyllonorycterblancardella, Pieris rapae, Plathypena scabra, Platynota idaeusalis,Plodia interpunctella, Plutella xylostella, Polychrosis viteana, Praysendocarpa, Prays oleae, Pseudaletia unipuncta, Pseudoplusia indudens,Rachiplusia nu, Scirpophaga incertulas, Sesamia inferens, Sesamianonagrioides, Setora nitens, Sitotroga cerealella, Sparganothispilleriana, Spodoptera exigua, Spodoptera frugiperda, Spodopteraeridania, Thecla basilides, Tinea pellionella, Tineola bisselliella,Trichoplusia ni, Tuta absoluta, Zeuzera coffeae, and Zeuzea pyrina.

(12) Order Mallophaga. A non-exhaustive list of particular generaincludes, but is not limited to, Anaticola spp., Bovicola spp.,Chelopistes spp., Goniodes spp., Menacanthus spp., and Trichodectes spp.A non-exhaustive list of particular species includes, but is not limitedto, Bovicola bovis, Bovicola caprae, Bovicola ovis, Chelopistesmeleagridis, Goniodes dissimilis, Goniodes gigas, Menacanthusstramineus, Menopon gallinae, and Trichodectes canis.

(13) Order Orthoptera. A non-exhaustive list of particular generaincludes, but is not limited to, Melanoplus spp. and Pterophylla spp. Anon-exhaustive list of particular species includes, but is not limitedto, Acheta domesticus, Anabrus simplex, Gryllotalpa africana,Gryllotalpa australis, Gryllotalpa brachyptera, Gryllotalpa hexadactyla,Locusta migratoria, Microcentrum retinerve, Schistocerca gregaria, andScudderia furcata.

(14) Order Psocoptera. A non-exhaustive list of particular speciesincludes, but is not limited to, Liposcelis decolor, Liposcelisentomophila, Lachesilla quercus, and Trogium pulsatorium.

(15) Order Siphonaptera. A non-exhaustive list of particular speciesincludes, but is not limited to, Ceratophyllus gallinae, Ceratophyllusniger, Ctenocephalides canis, Ctenocephalides felis, and Pulex irritans.

(16) Order Thysanoptera. A non-exhaustive list of particular generaincludes, but is not limited to, Caliothrips spp., Frankliniella spp.,Scirtothrips spp., and Thrips spp. A non-exhaustive list of particularspecies includes, but is not limited to, Caliothrips phaseoli,Frankliniella bispinosa, Frankliniella fusca, Frankliniellaoccidentalis, Frankliniella schultzei, Frankliniella tritici,Frankliniella williamsi, Heliothrips haemorrhoidalis, Rhipiphorothripscruentatus, Scirtothrips citri, Scirtothrips dorsalis, Taeniothripsrhopalantennalis, Thrips hawaiiensis, Thrips nigropilosus, Thripsorientalis, Thrips palmi, and Thrips tabaci.

(17) Order Thysanura. A non-exhaustive list of particular generaincludes, but is not limited to, Lepisma spp. and Thermobia spp.

(18) Order Acarina. A non-exhaustive list of particular genera includes,but is not limited to, Acarus spp., Aculops spp., Argus spp., Boophilusspp., Demodex spp., Dermacentor spp., Epitrimerus spp., Eriophyes spp.,Ixodes spp., Oligonychus spp., Panonychus spp., Rhizoglyphus spp., andTetranychus spp. A non-exhaustive list of particular species includes,but is not limited to, Acarapis woodi, Acarus siro, Aceria mangiferae,Aculops lycopersici, Aculus pelekassi, Aculus schlechtendali, Amblyommaamericanurn, Brevipalpus obovatus, Brevipalpus phoenicis, Dermacentorvariabilis, Dermatophagoides pteronyssinus, Eotetranychus carpini,Liponyssoides sanguineus, Notoedres cati, Oligonychus coffeae,Oligonychus ilicis, Ornithonyssus bacoti, Panonychus citri, Panonychusulmi, Phyllocoptruta oleivora, Polyphagotarsonemus latus, Rhipicephalussanguineus, Sarcoptes scabiei, Tegolophus perseaflorae, Tetranychusurticae, Tyrophagus longior, and Varroa destructor.

(19) Order Araneae. A non-exhaustive list of particular genera includes,but is not limited to, Loxosceles spp., Latrodectus spp., and Atrax spp.A non-exhaustive list of particular species includes, but is not limitedto, Loxosceles redusa, Latrodectus mactans, and Atrax robustus.

(20) Class Symphyla. A non-exhaustive list of particular speciesincludes, but is not limited to, Scutigerella immaculata.

(21) Subclass Collembola. A non-exhaustive list of particular speciesincludes, but is not limited to, Bourletiella hortensis, Onychiurusarmatus, Onychiurus fimetarius, and Sminthurus viridis.

(22) Phylum Nematoda. A non-exhaustive list of particular generaincludes, but is not limited to, Aphelenchoides spp., Belonolaimus spp.,Criconemella spp., Ditylenchus spp., Globodera spp., Heterodera spp.,Hirschmanniella spp., Hoplolaimus spp., Meloidogyne spp., Pratylenchusspp., and Radopholus spp. A non-exhaustive list of particular speciesincludes, but is not limited to, Dirofilaria immitis, Globodera pallida,Heterodera glycines, Heterodera zeae, Meloidogyne incognita, Meloidogynejavanica, Onchocerca volvulus, Pratylenchus penetrans, Radopholussimilis, and Rotylenchulus reniformis.

(23) Phylum Mollusca. A non-exhaustive list of particular speciesincludes, but is not limited to, Arion vulgaris, Cornu aspersum,Deroceras reticulatum, Limax flavus, Milax gagates, and Pomaceacanaliculata.

A particularly preferred pest group to control is sap-feeding pests.Sap-feeding pests, in general, have piercing and/or sucking mouthpartsand feed on the sap and inner plant tissues of plants. Examples ofsap-feeding pests of particular concern to agriculture include, but arenot limited to, aphids, leafhoppers, moths, scales, thrips, psyllids,mealybugs, stinkbugs, and whiteflies. Specific examples of Orders thathave sap-feeding pests of concern in agriculture include but are notlimited to, Anoplura and Hemiptera. Specific examples of Hemiptera thatare of concern in agriculture include, but are not limited to,Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Coccus spp.,Euschistus spp., Lygus spp., Macrosiphum spp., Nezara spp., andRhopalosiphum spp.

Another particularly preferred pest group to control is chewing pests.Chewing pests, in general, have mouthparts that allow them to chew onthe plant tissue including roots, stems, leaves, buds, and reproductivetissues (including, but not limited to flowers, fruit, and seeds).Examples of chewing pests of particular concern to agriculture include,but are not limited to, caterpillars, beetles, grasshoppers, andlocusts. Specific examples of Orders that have chewing pests of concernin agriculture include but are not limited to, Coleoptera andLepidoptera. Specific examples of Coleoptera that are of concern inagriculture include, but are not limited to, Anthonomus spp., Cerotomaspp., Chaetocnema spp., Colaspis spp., Cyclocephala spp., Diabroticaspp., Hypera spp., Phyllophaga spp., Phyllotreta spp., Sphenophorusspp., Sitophilus spp.

The phrase “pesticidally effective amount” means the amount of apesticide needed to achieve an observable effect on a pest, for example,the effects of necrosis, death, retardation, prevention, removal,destruction, or otherwise diminishing the occurrence and/or activity ofa pest in a locus. This effect may come about when pest populations arerepulsed from a locus, pests are incapacitated in, or around, a locus,and/or pests are exterminated in, or around, a locus. Of course, acombination of these effects can occur. Generally, pest populations,activity, or both are desirably reduced more than fifty percent,preferably more than 90 percent, and most preferably more than 99percent. In general, a pesticidally effective amount, for agriculturalpurposes, is from about 0.0001 grams per hectare to about 5000 grams perhectare, preferably from about 0.0001 grams per hectare to about 500grams per hectare, and it is even more preferably from about 0.0001grams per hectare to about 50 grams per hectare.

DETAILED DESCRIPTION OF THIS DISCLOSURE

This document discloses molecules of Formula One

wherein:

-   -   (A) R¹ is selected from the group consisting of H, F, Cl, Br, I,        CN, NO₂, SF₅, and (C₁-C₃)haloalkyl;    -   (B) R² is selected from the group consisting of H, F, Cl, Br, I,        CN, NO₂, SF₅, and (C₁-C₃)haloalkyl;    -   (C) R³ is selected from the group consisting of H, F, Cl, Br, I,        CN, NO₂, SF₅, and (C₁-C₃)haloalkyl;    -   (D) R⁴ is selected from the group consisting of H, F, Cl, Br, I,        CN, NO₂, SF₅, and (C₁-C₃)haloalkyl;    -   (E) R⁵ is selected from the group consisting of H, F, Cl, Br, I,        CN, NO₂, SF₅, and (C₁-C₃)haloalkyl;    -   (F) R⁶ is H;    -   (G) R⁷ is selected from the group consisting of F, Cl, and Br;    -   (H) R⁸ is selected from the group consisting of F, Cl, and Br;    -   (I) R⁹ is H;    -   (J) Q¹ is selected from the group consisting of O and S;    -   (K) Q² is selected from the group consisting of O and S;    -   (L) R¹⁰ is selected from the group consisting of H, (C₁-C₃)        alkyl, (C₂-C₃)alkenyl, (C₂-C₃)alkynyl,        (C₁-C₃)alkylO(C₁-C₃)alkyl, and (C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl;    -   (M) R¹¹ is selected from the group consisting of H, F, Cl, Br,        I, CN, NO₂, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy;    -   (N) R¹² is selected from the group consisting of H, F, Cl, Br,        I, CN, NO₂, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy;    -   (O) R¹³ is selected from the group consisting of H, F, Cl, Br,        I, CN, NO₂, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy;    -   (P) R¹⁴ is selected from the group consisting of H, F, Cl, Br,        I, CN, NO₂, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy;    -   (Q) X³ is:        -   (1) N(R^(15a))(R^(15b)) wherein            -   (a) said R^(15a) is selected from the group consisting                of H, (C₁-C₃)alkyl, (C₂-C₃)alkenyl, (C₂-C₃)alkynyl,                (C₁-C₃)haloalkyl, (C₁-C₃)alkylphenyl,                (C₁-C₃)alkylO(C₁-C₃)alkyl,                (C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl, and C(═O)(C₁-C₃)alkyl,                and            -   (b) said R^(15b) is a substituted or unsubstituted                phenyl, said substituted phenyl has one or more                substituents selected from the group consisting of H, F,                Cl, Br, I, CN, NO₂, NH₂, OH, SF₅, (C₁-C₃)alkyl,                (C₁-C₃)haloalkyl, (C₂-C₃)alkenyl, (C₂-C₃)haloalkenyl,                (C₁-C₃)alkoxy, (C═O)O(C₁-C₃)alkyl, O(C═O)(C₁-C₃)alkyl,                N(R^(15c))₂, N═CHN(R^(15c))(X⁴), N(R^(15c))C(═O)O(X⁴),                N(R^(15c))S(═O)₂(X⁴), N(S(═O)₂(C₁-C₃)alkyl)₂,                N(R^(15c))C(═O)N(R^(15c))₂, N(R^(15c))C(═O)N(R^(15c))X⁴,                N(R^(15c))C(═S)N(R^(15c))₂, N(R^(15c))C(═S)N(R^(15c))X⁴,                N(R^(15c))(C₁-C₃)alkylX⁴,                N(R^(15c))(CH(O(C₁-C₃)alkyl)₂),                N(R^(15c))((C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl),                N(R^(15c))((C₁-C₃)alkylC(═O)N(R^(15c))₂),                N(R^(15c))C(═O)(R^(15c)), N(R^(15c))C(═O)X⁴,                N(R^(15c))(C(═O))₂X⁴, N(R^(15c))(C(═O))₂OX⁴,                N(R^(15c))(C(═O))₂N(R^(15c))X⁴, N(C(═O)O(C₁-C₆)alkyl)₂,                N(R^(15c))C(═O)O(C₁-C₆)alkyl,                N(R^(15C)(C(═O)N(R^(15c))C(═O)O(R^(15c)),                N(R^(15c))(C(═O)O(C₁-C₆)alkyl),                N(R^(15c))(C(═O)O(C₁-C₆)haloalkyl),                N((C₁-C₃)alkylOC(═O)(C₁-C₆)alkyl)(C(═O)(C₁-C₆)alkyl),                N((C₁-C₃)alkylO(C₁-C₆)alkyl)(C(═O)O(C₁-C₆)alkyl),and                N(R^(15c))C(═S)X⁴,                -   (1) said R^(15c) is each independently selected from                    the group consisting of H, (C₁-C₃)alkyl,                    (C₂-C₃)alkenyl, (C₂-C₃)alkynyl, (C₁-C₃)haloalkyl,                    (C₂-C₃)haloalkenyl, (C₁-C₃)alkylphenyl,                    (C₁-C₃)alkylO(C₁-C₃)alkyl,                    (C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl, C(═O)(C₁-C₃)alkyl,                    and phenyl, optionally, for N(R^(15c))₂ said                    N(R^(15c))₂ is a heterohydrocarbyl ring containing                    one nitrogen ring atom and three to five carbon ring                    atoms, where said ring may be saturated or                    unsaturated,                -   (2) said X⁴ is selected from the group consisting of                    (C₁-C₆)alkyl, (C₁-C₆)haloalkyl,                    (C₁-C₃)alkylO(C₁-C₃)alkyl, O(C₁-C₆)alkyl,                    (C₃-C₆)cycloalkyl, (C₁-C₆)alkylphenyl, phenyl, aryl,                    and heterocyclyl, each of which may be substituted                    with one or more of substituents selected from the                    group consisting of F, Cl, Br, I, CN, OH, NO₂, NH₂,                    oxo, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, NH(C₁-C₃)alkyl,                    N((C₁-C₃)alkyl)₂, O(C₁-C₆)alkyl, O(C₁-C₆)haloalkyl,                    N(R^(15c))C(═O)O(C₁-C₆)alkyl,                    N(R^(15c))S(═O)₂(R^(15c)), S(═O)₂(R^(15c)),                    (C₁-C₃)alkylO(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl,            -   wherein (1)(a) and (1)(b) each said alkyl, alkenyl,                alkynyl, cycloalkyl, phenyl, aryl, and heterocyclyl, may                be substituted with one or more substituents selected                from the group consisting of F, Cl, Br, I, CN, OH, NO₂,                NH₂, NH(C₁-C₃)alkyl, N((C₁-C₃)alkyl)₂, O(C₁-C₆)alkyl,                (C₁-C₃)alkylO(C₁-C₃)alkyl, and (C₃-C₆)cycloalkyl;        -   (2) N(R^(16a))(R^(16b)) wherein            -   (a) said R^(16a) is selected from the group consisting                of H, (C₁-C₃)alkyl, (C₂-C₃)alkenyl, (C₂-C₃)alkynyl,                (C₁-C₃)haloalkyl, (C₁-C₃)alkylO(C₁-C₃)alkyl,                (C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl, and C(═O)(C₁-C₃)alkyl,            -   (b) said R^(16b) is a substituted or unsubstituted                (C₁-C₈)alkyl, said substituted (C₁-C₈)alkyl has one or                more substituents selected from the group consisting of                F, Cl, Br, I, CN, NO₂, O(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,                (C₁-C₈)alkylphenyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,                S(C₁-C₈)alkyl, S(O)(C₁-C₈)alkyl, S(O)₂(C₁-C₈)alkyl,                Ophenyl, O(C₂-C₈)alkenyl,                O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl, O(C₁-C₈)alkylphenyl,                O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl, O(C₁-C₈)alkyl,                C(═O)O(C₁-C₈)alkyl, OC(═O)(C₁-C₈)alkyl,                C(═O)N(R^(16a))(C₁-C₈)alkyl,                N(R^(16a))C(═O)(C₁-C₈)alkyl, S(C₁-C₈)alkyl,                S(O)(C₁-C₈)alkyl, S(O)₂(C₁-C₈)alkyl, S(O)₂NH₂, and                N(R^(16a))S(O)₂(C₁-C₈)alkyl,            -   wherein (2)(a) and (2)(b) each alkyl, alkenyl, alkynyl,                cycloalkyl, and phenyl, may be substituted with one or                more substituents selected from the group consisting of                F, Cl, Br, I, CN, OH, NH₂, NO₂, (C₁-C₈)alkyl,                (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, N((C₁-C₈)alkyl)₂, and                C(═O)O(C₁-C₈)alkyl;        -   (3) N(R^(17a))(N(R^(17b))(R^(17c)) wherein            -   (a) said R^(17a) is selected from the group consisting                of H, (C₁-C₃)alkyl, (C₂-C₃)alkenyl, (C₂-C₃)alkynyl,                (C₁-C₃)haloalkyl, (C₁-C₃)alkylO(C₁-C₃)alkyl,                (C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl, and C(═O)(C₁-C₃)alkyl,            -   (b) said R^(17b) is selected from the group consisting                of H, (C₁-C₃)alkyl, (C₂-C₃)alkenyl, (C₂-C₃)alkynyl,                (C₁-C₃)haloalkyl, (C₁-C₃)alkylO(C₁-C₃)alkyl,                (C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl, and C(═O)(C₁-C₃)alkyl,            -   (c) said R^(17c) is selected from the group consisting                of H, substituted or unsubstituted phenyl, substituted                or unsubstituted heterocyclyl, substituted or                unsubstituted (C₁-C₈)alkyl, substituted or unsubstituted                (C₃-C₈)cycloalkyl, C(═O)X⁵, and C(═S)X⁵,                -   (1) said X⁵ is selected from the group consisting of                    substituted or unsubstituted phenyl, substituted or                    unsubstituted heterocyclyl, substituted or                    unsubstituted (C₁-C₈)alkyl, O(C₁-C₈)alkyl,                    O(C₁-C₈)haloalkyl, O(substituted and                    unsubstituted)phenyl, N(R^(17a))(C₁-C₈)alkyl,                    N(R^(17a))(C₁-C₈)haloalkyl,                    N(R^(17a))(C₃-C₈)cycloalkyl, N(R^(17a)) (substituted                    and unsubstituted phenyl), and (C₃-C₆)cycloalkyl,                -   (2) said substituted phenyl in (3)(c) has one or                    more substituents selected from the group consisting                    of F, Cl, Br, I, CN, NO₂, OH, (C₁-C₃)alkoxy, and                    (C₁-C₃)alkyl,                -   (3) said substituted heterocyclyl in (3)(c) has one                    or more substituents selected from the group                    consisting of F, Cl, Br, I, CN, NO₂, OH,                    (C₁-C₃)alkoxy, and (C₁-C₃)alkyl,                -   (4) said substituted (C₁-C₈)alkyl in (3)(c) has one                    or more substituents selected from the group                    consisting of F, Cl, Br, I, CN, OH, NO₂, NH₂,                    O(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, phenyl,                    (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, S(C₁-C₈)alkyl,                    S(O)(C₁-C₈)alkyl, S(O)₂(C₁-C₈)alkyl, Ophenyl,                    O(C₂-C₈)alkenyl, O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl,                    O(C₁-C₈)alkylphenyl, O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl,                    C(═O)NH(C₁-C₈)alkyl, NHC(═O)(C₁-C₈)alkyl, S(O)₂NH₂,                    NH(C₁-C₃)alkyl, N((C₁-C₃)alkyl)₂,                -   (5) said substituted (C₃-C₈)cycloalkyl has one or                    more substituents selected from the group consisting                    of F, Cl, Br, I, CN, OH, (C₁-C₃)alkoxy, and                    (C₁-C₃)alkyl,            -   wherein (2)(a), (2)(b), and (2)(c) each alkyl, alkenyl,                alkynyl, cycloalkyl, haloalkyl, phenyl, and                heterocyclyl, may be optionally substituted with one or                more substituents selected from the group consisting of                F, Cl, Br, I, CN, OH, NH₂, NO₂, (C₁-C₈)alkyl,                (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, N((C₁-C₈)alkyl)₂, and                C(═O)O(C₁-C₈)alkyl, optionally (N(R^(17b))(R^(17c)) is a                heterohydrocarbyl ring containing one nitrogen ring atom                and three to five carbon ring atoms, where said ring may                be saturated or unsaturated;        -   (4) N(R_(18a))(N═C(R^(18b))(R^(18c))            -   (a) said R^(18a) is selected from the group consisting                of H, (C₁-C₃)alkyl, (C₂-C₃)alkenyl, (C₂-C₃)alkynyl,                (C₁-C₃)alkylO(C₁-C₃)alkyl,                (C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl, and C(═O)(C₁-C₃)alkyl,            -   (b) said R^(18b) is selected from the group consisting                of H and (C₁-C₃)alkyl,            -   (c) said R^(18c) is selected from the group consisting                of substituted or unsubstituted phenyl, substituted or                unsubstituted heterocyclyl, substituted or unsubstituted                (C₁-C₈)alkyl, substituted or unsubstituted                (C₃-C₈)cycloalkyl,                -   (1) said substituted phenyl in (4)(c) has one or                    more substituents selected from the group consisting                    of F, Cl, Br, I, CN, NO₂, OH, (C₁-C₃)alkoxy,                    (C₁-C₃)alkyl, (C₁-C₃)haloalkoxy, and                    (C₁-C₃)haloalkyl,                -   (2) said substituted heterocyclyl in (4)(c) has one                    or more substituents selected from the group                    consisting of F, Cl, Br, I, CN, NO₂, OH,                    (C₁-C₃)alkoxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkoxy, and                    (C₁-C₃)haloalkyl,                -   (3) said substituted (C₁-C₈)alkyl has one or more                    substituents selected from the group consisting of                    F, Cl, Br, I, CN, NO₂, O(C₁-C₈)alkyl,                    (C₃-C₈)cycloalkyl, phenyl, (C₂-C₈)alkenyl,                    (C₂-C₈)alkynyl, S(C₁-C₈)alkyl, S(O)(C₁-C₈)alkyl,                    S(O)₂(C₁-C₈)alkyl, Ophenyl, O(C₂-C₈)alkenyl,                    O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl, O(C₁-C₈)alkylphenyl,                    O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl, C(═O)NH(C₁-C₈)alkyl,                    NHC(═O)(C₁-C₈)alkyl, and S(O)₂NH₂,                -   (4) said substituted (C₃-C₈)cycloalkyl has one or                    more substituents selected from the group consisting                    of F, Cl, Br, I, CN, OH, (C₁-C₃)alkoxy, and                    (C₁-C₃)alkyl,            -   wherein (4)(a), (4)(b), and (4)(c) each alkyl, alkenyl,                alkynyl, cycloalkyl, haloalkyl, phenyl, and heterocyclyl                may be substituted with one or more substituents                selected from the group consisting of F, Cl, Br, I, CN,                OH, NH₂, NO₂, (C₁-C₈)alkyl, (C₁-C₈)alkoxy,                (C₁-C₈)haloalkyl, N((C₁-C₈)alkyl)₂, and                C(═O)O(C₁-C₈)alkyl, optionally C(R^(18b))(R^(18c)) is a                hydrocarbyl ring containing three to five carbon ring                atoms, where said ring may be saturated or unsaturated,                optionally, one or more of said carbon ring atoms may                instead be nitrogen, oxygen, or sulfur atom;    -   and N-oxides, agriculturally acceptable acid addition salts,        salt derivatives, solvates, ester derivatives, crystal        polymorphs, isotopes, resolved stereoisomers, tautomers,        pro-insecticides, of the molecules of Formula One.

In another embodiment a molecule according to Formula One wherein saidmolecule has the following formula

In another embodiment a molecule according to Formula One and FormulaTwo wherein R¹ is selected from the group consisting of H, F, Cl, Br,SF₅, and CF₃.

In another embodiment a molecule according to Formula One and FormulaTwo wherein R² is selected from the group consisting of H, F, Cl, Br,SF₅, and CF₃.

In another embodiment a molecule according to Formula One and FormulaTwo wherein R³ is selected from the group consisting of H, F, Cl, Br,SF₅, and CF₃.

In another embodiment a molecule according to Formula One and FormulaTwo wherein R⁴ is selected from the group consisting of H, F, Cl, Br,SF₅, and CF₃.

In another embodiment a molecule according to Formula One and FormulaTwo wherein R⁵ is selected from the group consisting of H, F, Cl, Br,SF₅, and CF₃.

In another embodiment a molecule according to Formula One and FormulaTwo wherein at least one of R², R³, and R⁴, is SF₅.

In another embodiment a molecule according to Formula One and FormulaTwo wherein R⁷ is Cl.

In another embodiment a molecule according to Formula One and FormulaTwo wherein R⁸ is Cl.

In another embodiment a molecule according to Formula One and FormulaTwo wherein R⁷, and R⁸ are not the same. In another embodiment amolecule according to Formula One and Formula Two wherein Q¹ is O.

In another embodiment a molecule according to Formula One and FormulaTwo wherein Q² is O.

In another embodiment a molecule according to Formula One and FormulaTwo wherein R¹⁰ is H.

In another embodiment a molecule according to Formula One and FormulaTwo wherein R¹¹ is H.

In another embodiment a molecule according to Formula One and FormulaTwo wherein R¹² is selected from the group consisting of H, F, Cl, CH₃,and CF₃.

In another embodiment a molecule according to Formula One and FormulaTwo wherein R¹³ is selected from the group consisting of F, Cl, CH₃, andOCH₃.

In another embodiment a molecule according to Formula One and FormulaTwo wherein R¹⁴ is selected from the group consisting of H, F, and Cl.

In another embodiment a molecule according to Formula One and FormulaTwo wherein:

R¹ is selected from the group consisting of H, F, Cl, Br, SF₅, and CF₃;

R² is selected from the group consisting of H, F, Cl, Br, SF₅, and CF₃;

R³ is selected from the group consisting of H, F, Cl, Br, SF₅, and CF₃;

R⁴ is selected from the group consisting of H, F, Cl, Br, SF₅, and CF₃;

R⁵ is selected from the group consisting of H, F, Cl, Br, SF₅, and CF₃;

R⁷ is Cl;

R⁸ is Cl;

Q¹ is O;

Q² is O;

R¹⁰ is H;

R¹¹ is H;

R¹² is selected from the group consisting of H, F, Cl, CH₃, and CF₃;

R¹³ is selected from the group consisting of F, Cl, CH₃, and OCH₃; and

R¹⁴ is selected from the group consisting of H, F, and Cl.

In another embodiment a molecule according to Formula One and FormulaTwo wherein X³ is N(R^(15a))(R^(15b)).

In another embodiment a molecule according to Formula One and FormulaTwo wherein X³ is N(R^(15a))(R^(15b)) and said R^(15b) is selected fromthe group consisting of N(R^(15c))C(═O)(R^(15c)) and N(R^(15c))C(═O)X⁴,said R^(15c) are each independently selected from the group consistingof (C₁-C₃)alkyl, (C₂-C₃)alkenyl, (C₁-C₃)haloalkyl, and(C₁-C₃)alkylO(C₁-C₃)alkyl, said X⁴ is selected from the group consistingof (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, and (C₁-C₃)alkylO(C₁-C₃)alkyl, andeach said alkyl, haloalkyl, and alkenyl, may be substituted with one ormore substituents selected from the group consisting of F, Cl, CN, and(C₃-C₆)cycloalkyl. For avoidance of doubt this includes, for example,substituting a haloalkyl, which includes the term “alkyl” with one ormore substituents, for example CN or (C₃-C₆)cycloalkyl.

In another embodiment a molecule according to Formula One and FormulaTwo wherein X³ is N(R^(16a))(R^(16b)).

In another embodiment a molecule according to Formula One and FormulaTwo wherein X3 is N(R^(17a))(N(R^(17b))(R^(17c)).

In another embodiment a molecule according to Formula One and FormulaTwo wherein X³ is N(R^(18a))(N═C(R^(18b))(R^(18c)).

In another embodiment a molecule selected from Table 2, preferably amolecule selected from the group consisting of F1007, F1079, F1108,F1147, F1185, F1234, F1241, F1246, F1247, F1248, F1250, F1460, F1465,F1593, F1598, F1613, F1627, F1657, F1694, F1696, F1697, F1702, F1703,F1704, F1708, F1711, F1740, F2016, F2017, F2021, F2027, F2039, F2042,F2078, and F2081.

The molecules of Formula One may exist in different geometric or opticalisomeric or different tautomeric forms. One or more centers of chiralitymay be present in which case molecules of Formula One may be present aspure enantiomers, mixtures of enantiomers, pure diastereomers ormixtures of diastereomers. It will be appreciated by those skilled inthe art that one stereoisomer may be more active than the otherstereoisomers. Individual stereoisomers may be obtained by knownselective synthetic procedures, by conventional synthetic proceduresusing resolved starting materials, or by conventional resolutionprocedures. There may be double bonds present in the molecule, in whichcase compounds of Formula One may exist as single geometric isomers (cisor trans, E or Z) or mixtures of geometric isomers (cis and trans, E andZ). Centers of tautomerisation may be present. This disclosure coversall such isomers, tautomers, and mixtures thereof, in all proportions.The structures disclosed in the present disclosure maybe drawn in onlyone geometric form for clarity, but are intended to represent allgeometric forms of the molecule.

Preparation of Molecules of Formula One Preparation of CyclopropylCarboxylic Acids

Stilbenes 1-1, wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁹ are as previouslydisclosed, may be treated with a base such as sodium hydroxide in thepresence of a carbene source such as chloroform or bromoform and a phasetransfer catalyst such as N-benzyl-N,N-diethylethanaminium chloride in apolar protic solvent such as water at temperatures from about 0° C. toabout 40° C. to provide diaryl cyclopropanes 1-2, wherein R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are as previously disclosed (Scheme 1, stepa). Alternatively, stilbenes 1-1, wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁹are as previously disclosed, may be treated with a salt such as sodiumiodide in the presence of a carbene source such astrimethyl(trifluoromethyl)silane in a polar aprotic solvent such astetrahydrofuran at temperatures from about 80° C. to about 120° C. undermicrowave irradiation conditions to provide diaryl cyclopropanes 1-2,wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are as previouslydisclosed (Scheme 1, step a). Treatment of diaryl cyclopropanes 1-2 witha transition metal such as ruthenium(III) chloride in the presence of astoichiometric oxidant such as sodium periodate in a solvent mixturepreferably water, ethyl acetate, and acetonitrile at temperatures fromabout 0° C. to about 40° C. may provide cyclopropyl carboxylic acids1-3, wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are as previouslydisclosed (Scheme 1, step b).

Preparation of Stilbenes

Stilbenes 1-1 may be prepared by several different methods as outlinedin Scheme 2. Phenyl carbonyls 2-1, wherein R¹, R², R³, R⁴, R⁵, and R⁶are as previously disclosed, may be treated with alkoxy benzylphosphonates 2-2 in the presence of a base such as sodium methoxide in apolar aprotic solvent such as N,N-dimethylformamide at temperatures fromabout −10° C. to about 30° C. and subsequently heated to 40° C. to about80° C. to provide stilbenes 1-1 (Scheme 2, step a). Aryl halides 2-3,wherein R¹, R², R³, R⁴, and R⁵ are as previously disclosed, may betreated with vinylbenzenes 2-4, wherein R⁶ and R⁹ are as previouslydisclosed, in the presence of a transition metal catalyst such aspalladium(II) acetate and a bisphosphine ligand such as1,1′-bis(diphenylphosphino)ferrocene in a basic solvent such astriethylamine at temperatures from about 60° C. to about 100° C. toprovide stilbenes 1-1 (Scheme 2, step b).

In yet another embodiment, stilbenes 1-1 may also be prepared by theWittig olefination method (Chalal, M.; Vervandier-Fasseur, D.; Meunier,P.; Cattey, H.; Hierso, J.-C. Tetrahedron 2012, 68, 3899-3907) asoutlined in Scheme 2.5. Phenyl carbonyls 2-1, wherein R¹, R², R³, R⁴,and R⁵ are as previously disclosed and R⁶ is H, may be treated withalkoxy benzyl triphenylphosphonium chlorides 2.5-2 in the presence of abase such as n-butyl lithium in a polar aprotic solvent such astetrahydrofuran at temperatures from about −78° C. to ambienttemperature to provide stilbenes 1-1 (Scheme 2.5, step a).

Preparation of Cyclopropyl Amides

Cyclopropyl amides 3-3, wherein Q¹ is O, and R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, Q², and X³ are as previously disclosed,may be prepared by treatment with amines or amine salts 3-2, whereinR¹⁰, R¹¹, R¹², R¹³, R¹⁴, Q², and X³ are as previously disclosed, andactivated carboxylic acids 3-1, wherein A is an activating group, andR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are as previously disclosed, witha base, such as triethylamine, diisopropylethylamine,4-methylmorpholine, or 4-dimethylaminopyridine in an anhydrous aproticsolvent such as dichloromethane, tetrahydrofuran, 1,2-dichloroethane,dimethylformamide, or any combination thereof, at temperatures betweenabout 0° C. and about 120° C. (Scheme 3, step a).

Carboxylic acids 3-1, wherein A is an activating group, may be an acidhalide, such as an acid chloride, an acid bromide, or an acid fluoride;a carboxylic ester, such as a para-nitrophenyl ester, apentafluorophenyl ester, an ethyl (hydroxyimino)cyanoacetate ester, amethyl ester, an ethyl ester, a benzyl ester, an N-hydroxysuccinimidylester, a hydroxybenzotriazol-1-yl ester, or a hydroxypyridyltriazol-1-ylester; an O-acylisourea; an acid anhydride; or a thioester. Acidchlorides may be prepared from the corresponding carboxylic acids bytreatment with a dehydrating chlorinating reagent, such as oxalylchloride or thionyl chloride. Activated carboxylic esters 3-1 may beprepared from carboxylic acids in situ with a uronium salt, such as1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), or(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate (COMU). Activated carboxylic esters 3-1 may also beprepared from carboxylic acids in situ with a phosphonium salt such asbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBop). Activated carboxylic esters 3-1 may also be prepared fromcarboxylic acids in situ with a coupling reagent such as1-(3-dimethylamino propyl)-3-ethylcarbodiimide, ordicyclohexylcarbodiimide in the presence of a triazole such ashydroxybenzotriazole.monohydrate (HOBt) or 1-hydroxy-7-azabenzotriazole(HOAt). O-Acylisoureas may be prepared with a dehydrating carbodimidesuch as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide ordicyclohexylcarbodiimide. Activated carboxylic esters 3-1 may also beprepared from carboxylic acids in situ with a coupling reagent such as2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP) in thepresence of a triazole such as 1-hydroxy-7-azabenzotriazole (HOAt).Activated carboxylic esters 3-1 may also be prepared from carboxylicacids in situ with a coupling reagent such as2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®)in the presence of a base such as pyridine.

Cyclopropyl amides 3-3, wherein R^(15b) contains a sulfide and R^(15a)is as previously disclosed, may be oxidized to the correspondingsulfoxide or sulfone by treatment with about one equivalent ofmeta-chloroperoxybenzoic acid in a polar aprotic solvent such asdichloromethane (sulfoxide) or about two equivalents ofmeta-chloroperoxybenzoic acid (sulfone) at temperatures between about 0°C. to about 40° C. Alternatively, cyclopropyl amides 3-3, whereinR^(15b) contains a sulfide may be oxidized to the correspondingsulfoxide or sulfone by treatment with one equivalent of sodiumperborate in a protic solvent such as acetic acid (sulfoxide) or twoequivalents of sodium perborate (sulfone). Preferably, the oxidationwill be performed at temperatures between about 40° C. to about 100° C.using about 1.5 equivalents of sodium perborate to providechromatographically separable mixtures of sulfoxide and sulfonecyclopropyl amides 3-3. Alternatively, cyclopropyl amides 3-3 containinga sulfide may be oxidized to the corresponding sulfilimine by treatingwith about one equivalent of an amine such as cyanamide, about oneequivalent of a base such as potassium tert-butoxide, and between oneand two equivalents of an oxidant such as N-bromosuccinimide in a polarprotic solvent such as methanol at temperatures between about 0° C. toabout 40° C. The sulfilimine may be further oxidized to thecorresponding sulfoximine by treatment with about one equivalent ofmeta-chloroperoxybenzoic acid and about two equivalents of potassiumcarbonate in a mixture of solvents such as 2:1:1ethanol:dichloromethane:water at temperatures between about 0° C. toabout 40° C.

Cyclopropyl amides 3-3, wherein R³ is NO₂ may be reduced to thecorresponding NH₂ by treatment with an acid source, such as ammoniumchloride, and iron in a polar protic solvent, such as methanol, water,or any combination thereof, at temperatures from about 20° C. to about60° C.

Amines or amine salts 3-2, wherein Q² is O may be treated directly witha source of sulfur, such as phosphorus pentasulfide or2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide(Lawesson's reagent) with or without additives such as1,1,1,3,3,3-hexamethyldisoloxane, in an aprotic solvent chosen fromtetrahydrofuran, dichloromethane, chloroform, toluene, or pyridine, attemperatures from about 40° C. to about 120° C. to provide amines oramine salts 3-2, wherein Q² is S.

Cyclopropyl amides 4-3, wherein Q² is O, and R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and X³ are as previously disclosed,may be prepared by treatment with amines or amine salts 4-2, wherein X³is as previously disclosed, and activated carboxylic acids 4-1, whereinA is an activating group, and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Q¹,R¹⁰, R¹¹, R¹², R¹³, and R¹⁴ are as previously disclosed, with a base,such as triethylamine, diisopropylethylamine, 4-methylmorpholine,pyridine, or 4-dimethylaminopyridine in an anhydrous aprotic solventsuch as dichloromethane, tetrahydrofuran, 1,2-dichloroethane,dimethylformamide, or any combination thereof, at temperatures betweenabout 0° C. and about 120° C. (Scheme 4, step a).

Activated carboxylic acids 4-1 may be an acid halide, such as an acidchloride, an acid bromide, or an acid fluoride; a carboxylic ester, suchas a para-nitrophenyl ester, a pentafluorophenyl ester, an ethyl(hydroxyimino)cyanoacetate ester, a methyl ester, an ethyl ester, abenzyl ester, an N-hydroxysuccinimidyl ester, a hydroxybenzotriazol-1-ylester, or a hydroxypyridyltriazol-1-yl ester; an O-acylisourea; an acidanhydride; or a thioester. Acid chlorides may be prepared from thecorresponding carboxylic acids by treatment with a dehydratingchlorinating reagent, such as oxalyl chloride or thionyl chloride.Activated carboxylic esters 4-1 may be prepared from carboxylic acids insitu with a uronium salt, such as1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), or(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate (COMU). Activated carboxylic esters 4-1 may also beprepared from carboxylic acids in situ with a phosphonium salt such asbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBop). Activated carboxylic esters 4-1 may also be prepared fromcarboxylic acids in situ with a coupling reagent such as1-(3-dimethylamino propyl)-3-ethylcarbodiimide, ordicyclohexylcarbodiimide in the presence of a triazole such ashydroxybenzotriazole.monohydrate (HOBt) or 1-hydroxy-7-azabenzotriazole(HOAt). O-Acylisoureas may be prepared with a dehydrating carbodimidesuch as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide ordicyclohexylcarbodiimide. Activated carboxylic esters 4-1 may also beprepared from carboxylic acids in situ with a coupling reagent such as2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP) in thepresence of a triazole such as 1-hydroxy-7-azabenzotriazole (HOAt).Activated carboxylic esters 4-1 may also be prepared from carboxylicacids in situ with a coupling reagent such as2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®)in the presence of a base such as pyridine.

Cyclopropyl amides 5-2, wherein X³ is N(R^(15a))(R^(15b)) and R^(15b) isa substituted phenyl having one or more substituents includingN(R^(15c))₂, wherein one of R^(15c) is a (C₁-C₃)alkylphenyl; Q² is O,R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR^(15a) are as previously disclosed, may be prepared by treatment ofamines 5-1, wherein X³ is N(R^(15a))(R^(15b)) and R^(15b) is asubstituted phenyl having one or more substituents includingN(R^(15c))₂, wherein R^(15c) is H; Q² is O, R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R^(15a) are as previouslydisclosed, with an aldehyde such as benzaldehyde in the presence of areducing agent such as sodium cyanoborohydride in a solvent such asmethanol, with or without an acid, such as acetic acid, at about roomtemperature (Scheme 5, step a).

Cyclopropyl amides 5-4, wherein X³ is N(R^(15a))(R^(15b)) and R^(15b) isa substituted phenyl having one or more substituents includingN(R^(15c))₂, wherein one or more of R^(15c) is (C₁-C₃)alkyl; Q² is O,R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR^(15a) are as previously disclosed, may be prepared by treatment ofamines 5-1, wherein X³ is N(R^(15a))(R^(15b)) and R^(15b) is asubstituted phenyl having one or more substituents includingN(R^(15c))₂, wherein R^(15c) is H; Q² is O, R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R^(15a) are as previouslydisclosed, with an alkylating agent 5-3 such as an alkyl halide in thepresence of a base, such as triethylamine, diisopropylethylamine,4-methylmorpholine, 4-dimethylaminopyridine, or pyridine, in ananhydrous aprotic solvent such as dichloromethane, tetrahydrofuran,1,2-dichloroethane, N,N-dimethylformamide, or any combination thereof,at temperatures between about 0° C. and about 120° C. (Scheme 5, stepb).

Cyclopropyl amides 5-6, wherein X³ is N(R^(15a))(R^(15b)) and R^(15b) isa substituted phenyl having one or more substituents includingN(R^(15c))C(═O)X⁴; Q² is O, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Q¹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, and R^(15a) are as previously disclosed, may beprepared by treatment of amines 5-1, wherein X³ is N(R^(15a))(R^(15b))and R^(15b) is a substituted phenyl having one or more substituentsincluding N(R^(15c))₂, wherein R^(15c) is H; Q² is O, R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R^(15a) are aspreviously disclosed, with an activated carboxylic acid 5-5 wherein A isan activating group and a base, such as triethylamine,diisopropylethylamine, 4-methylmorpholine, 4-dimethylaminopyridine, orpyridine, in an anhydrous aprotic solvent such as dichloromethane,tetrahydrofuran, 1,2-dichloroethane, N,N-dimethylformamide, or anycombination thereof, at temperatures between about 0° C. and about 120°C. (Scheme 5, step c).

Activated carboxylic acids 5-5, may be an acid halide, such as an acidchloride, an acid bromide, an acid fluoride, or a chloroformate; acarboxylic ester, such as a p-nitrophenyl ester, a pentafluorophenylester, an ethyl (hydroxyimino)cyanoacetate ester, a methyl ester, anethyl ester, a benzyl ester, an N-hydroxysuccinimidyl ester, ahydroxybenzotriazol-1-yl ester, or a hydroxypyridyltriazol-1-yl ester;an O-acylisourea; an acid anhydride; or a thioester. Acid chlorides maybe prepared from the corresponding carboxylic acids by treatment with adehydrating chlorinating reagent, such as oxalyl chloride or thionylchloride. Activated carboxylic esters 5-5 may be prepared fromcarboxylic acids in situ with a uronium salt, such as1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), or(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate (COMU). Activated carboxylic esters 5-5 may also beprepared from carboxylic acids in situ with a phosphonium salt such asbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBop). Activated carboxylic esters 5-5 may also be prepared fromcarboxylic acids in situ with a coupling reagent, such as1-(3-dimethylamino propyl)-3-ethylcarbodiimide ordicyclohexylcarbodiimide, in the presence of a triazole such ashydroxybenzotriazole.monohydrate (HOBt) or 1-hydroxy-7-azabenzotriazole(HOAt). O-Acylisoureas may be prepared with a dehydrating carbodimidesuch as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide ordicyclohexylcarbodiimide. Activated carboxylic esters 5-5 may also beprepared from carboxylic acids in situ with a coupling reagent such as2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP) in thepresence of a triazolol such as 1-hydroxy-7-azabenzotriazole (HOAt).Activated carboxylic esters 5-5 may also be prepared from carboxylicacids in situ with a coupling reagent such as2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®)in the presence of a base such as pyridine. In each 5-5 above, X⁴, is aspreviously defined.

Cyclopropyl amides 6-4, wherein X³ is N(R^(15a))(R^(15b)) and R^(15b) isa substituted phenyl having one or more substituents includingN(R^(15c))₂, wherein R^(15c) is H; Q² is O, R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R^(15a) are as previouslydisclosed, may be prepared by treatment of 6-1, wherein X³ isN(R^(15a))(R^(15b)) and R^(15b) is a substituted phenyl having one ormore substituents including NO₂; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Q¹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R^(15a) are as previously disclosed, with ametal such as palladium on carbon in the presence of a reducing agentsuch as hydrogen gas in a solvent such as ethyl acetate or with a metalsuch as iron in the presence of a reducing agent such as ammoniumchloride in a solvent mixture such as methanol and water at atemperature of about 25° C. to about 60° C. (Scheme 6, step a).

Alternatively, cyclopropyl amides 6-4, wherein X³ is N(R^(15a))(R^(15b))and R^(15b) is a substituted phenyl having one or more substituentsincluding N(R^(15c))₂, wherein R^(15c) is H; Q² is O, R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R^(15a) are aspreviously disclosed, may be prepared by treatment of 6-2, wherein X³ isN(R^(15a))(R^(15b)) and R^(15b) is a substituted phenyl having one ormore substituents including N(R^(15c))C(═O)O(C₁-C₆)alkyl wherein R^(15c)is H; Q² is O, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹²,R¹³, R¹⁴, and R^(15a) are as previously disclosed, with an anhydrousacid solution such as hydrochloric acid in 1,4-dioxane anddichloromethane at a temperature of about 25° C. (Scheme 6, step c).

Alternatively, cyclopropyl amides 6-4, wherein X³ is N(R^(15a))(R^(15b))and R^(15b) is a substituted phenyl having one or more substituentsincluding N(R^(15c))₂, wherein R^(15c) is H; Q² is O, R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R^(15a) are aspreviously disclosed, may be prepared by treatment of 6-3, wherein X³ isN(R^(15a))(R^(15b)) and R^(15b) is a substituted phenyl having one ormore substituents including N(C(═O)O(C₁-C₆)alkyl)₂; Q² is O, R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R^(15a) are aspreviously disclosed, with an anhydrous acid solution such ashydrochloric acid in 1,4-dioxane and dichloromethane at a temperature ofabout 25° C. (Scheme 6, step c).

Cyclopropyl amides 6-6, wherein X³ is N(R^(15a))(R^(15b)) and R^(15b) isa substituted phenyl having one or more substituents includingNH(R^(15c)) wherein R^(15c) is (C₁-C₃)alkyl; Q² is O, R¹, R², R³, R⁴,R⁵, R⁶, R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R^(15a) are aspreviously disclosed, may be prepared by treatment of 6-5 wherein X³ isN(R^(15a))(R^(15b)) and R^(15b) is a substituted phenyl having one ormore substituents including N(R^(15c))C(═O)O(C₁-C₆)alkyl wherein R^(15c)is (C₁-C₃)alkyl; R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹²,R¹³, R¹⁴, and R^(15a) are as previously disclosed, with an anhydrousacid solution such as hydrochloric acid in 1,4-dioxane anddichloromethane at a temperature of about 25° C. (Scheme 6, step d).

Cyclopropyl amides 7-2, wherein X³ is N(R^(15a))(R^(15b)) and R^(15b) isa substituted phenyl having one or more substituents including a(C₂-C₃)alkenyl or (C₂-C₃)haloalkenyl group; Q² is O; R¹, R², R³, R⁴, R⁵,R⁶, R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R^(15a) are aspreviously disclosed, may be prepared by treatment of aryl halides 7-1,wherein X³ is N(R^(15a))(R^(15b)) and R^(15b) is a substituted phenylhaving one or more substituents including Br or I; Q² is O; R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R^(15a) are aspreviously disclosed, with a stannane such as 7-2, wherein R^(15c) is a(C₂-C₃)alkenyl or (C₂-C₃)haloalkenyl group, in the presence of a metalcatalyst such as bis(triphenylphosphine)palladium(II) dichloride in anaprotic solvent like 1,4-dioxane at a temperature of about 90° C.(Scheme 7, step a), thereby replacing the Br or I with the(C₂-C₃)alkenyl or (C₂-C₃)haloalkenyl group.

Cyclopropyl amides 8-3, wherein Q¹ is O, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, Q², R^(17a), R^(17b), and R^(17c) are aspreviously disclosed, may be prepared by treatment of amines or aminesalts 8-2, wherein R¹⁰, R¹¹, R¹², R¹³, R¹⁴, Q², R^(17a), R^(17b), andR^(17c) are as previously disclosed, and activated carboxylic acids 8-1,wherein A is an activating group, and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,and R⁹ are as previously disclosed, with a base, such as triethylamine,diisopropylethylamine, 4-methylmorpholine, or 4-dimethylaminopyridine inan anhydrous aprotic solvent such as dichloromethane, tetrahydrofuran,1,2-dichloroethane, dimethylformamide, or any combination thereof, attemperatures between about 0° C. and about 120° C. (Scheme 8, step a).

Activated carboxylic acids 8-1 may be an acid halide, such as an acidchloride, an acid bromide, or an acid fluoride; a carboxylic ester, suchas a para-nitrophenyl ester, a pentafluorophenyl ester, an ethyl(hydroxyimino)cyanoacetate ester, a methyl ester, an ethyl ester, abenzyl ester, an N-hydroxysuccinimidyl ester, a hydroxybenzotriazol-1-ylester, or a hydroxypyridyltriazol-1-yl ester; an O-acylisourea; an acidanhydride; or a thioester. Acid chlorides may be prepared from thecorresponding carboxylic acids by treatment with a dehydratingchlorinating reagent, such as oxalyl chloride or thionyl chloride.Activated carboxylic esters 8-1 may be prepared from carboxylic acids insitu with a uronium salt, such as1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), or(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate (COMU). Activated carboxylic esters 8-1 may also beprepared from carboxylic acids in situ with a phosphonium salt such asbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBop). Activated carboxylic esters 8-1 may also be prepared fromcarboxylic acids in situ with a coupling reagent such as1-(3-dimethylamino propyl)-3-ethylcarbodiimide, ordicyclohexylcarbodiimide in the presence of a triazole such ashydroxybenzotriazole.monohydrate (HOBt) or 1-hydroxy-7-azabenzotriazole(HOAt). O-Acylisoureas may be prepared with a dehydrating carbodimidesuch as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide ordicyclohexylcarbodiimide. Activated carboxylic esters 8-1 may also beprepared from carboxylic acids in situ with a coupling reagent such as2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP) in thepresence of a triazole such as 1-hydroxy-7-azabenzotriazole (HOAt).Activated carboxylic esters 8-1 may also be prepared from carboxylicacids in situ with a coupling reagent such as2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®)in the presence of a base such as pyridine.

Cyclopropyl amides 9-3, wherein Q² is O, and R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R^(17a), R^(17b), and R^(17c) areas previously disclosed, may be prepared by treatment of hydrazines orhydrazine salts, 9-2, wherein R^(17a), R^(17b), and R^(17c) are aspreviously disclosed, and activated carboxylic acids 9-1, wherein A isan activating group, and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Q¹, R¹⁰,R¹¹, R¹², R¹³, and R¹⁴ are as previously disclosed, with a base, such astriethylamine, diisopropylethylamine, 4-methylmorpholine, or4-dimethylaminopyridine in an anhydrous aprotic solvent such asdichloromethane, tetrahydrofuran, 1,2-dichloroethane, dimethylformamide,or any combination thereof, at temperatures between about 0° C. andabout 120° C. (Scheme 9, step a).

Activated carboxylic acids 9-1 may be an acid halide, such as an acidchloride, an acid bromide, or an acid fluoride; a carboxylic ester, suchas a para-nitrophenyl ester, a pentafluorophenyl ester, an ethyl(hydroxyimino)cyanoacetate ester, a methyl ester, an ethyl ester, abenzyl ester, an N-hydroxysuccinimidyl ester, a hydroxybenzotriazol-1-ylester, or a hydroxypyridyltriazol-1-yl ester; an O-acylisourea; an acidanhydride; or a thioester. Acid chlorides may be prepared from thecorresponding carboxylic acids by treatment with a dehydratingchlorinating reagent, such as oxalyl chloride or thionyl chloride.Activated carboxylic esters 9-1 may be prepared from carboxylic acids insitu with a uronium salt, such as1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), or(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate (COMU). Activated carboxylic esters 9-1 may also beprepared from carboxylic acids in situ with a phosphonium salt such asbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBop). Activated carboxylic esters 9-1 may also be prepared fromcarboxylic acids in situ with a coupling reagent such as1-(3-dimethylamino propyl)-3-ethylcarbodiimide, ordicyclohexylcarbodiimide in the presence of a triazole such ashydroxybenzotriazole.monohydrate (HOBt) or 1-hydroxy-7-azabenzotriazole(HOAt). O-Acylisoureas may be prepared with a dehydrating carbodimidesuch as 1-(3-dimethylamino propyl)-3-ethylcarbodiimide ordicyclohexylcarbodiimide. Activated carboxylic esters 9-1 may also beprepared from carboxylic acids in situ with a coupling reagent such as2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP) in thepresence of a triazole such as 1-hydroxy-7-azabenzotriazole (HOAt).Activated carboxylic esters 9-1 may also be prepared from carboxylicacids in situ with a coupling reagent such as2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®)in the presence of a base such as pyridine.

Cyclopropyl amides 10-2, wherein Q² is O, R^(17a) and R^(17b) are H,(C₁-C₃)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, or (C₁-C₆)haloalkyl, andR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, and R¹⁴, areas previously disclosed, may be prepared by treatment of 10-1 wherein Q²is O, R^(17a), R^(17b), R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Q¹, R¹⁰,R¹¹, R¹², R¹³, and R¹⁴ are as previously disclosed, with an anhydrousacid solution such as hydrochloric acid in 1,4-dioxane anddichloromethane at a temperature of about 25° C. (Scheme 10, step a).

Cyclopropyl amides 10-4, wherein Q² is O, and R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R^(17a), and R^(17b) are aspreviously disclosed, and X⁵ is substituted or unsubstituted phenyl,substituted or unsubstituted heterocyclyl, substituted or unsubstituted(C₁-C₈)alkyl, O(C₁-C₈)alkyl, O(C₁-C₈)haloalkyl, (C₃-C₆)cycloalkyl, and O(substituted and unsubstituted)phenyl, may be prepared by treatment ofcyclopropyl amides 10-2, wherein Q² is O, and R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R^(14a), R^(17a), and R^(17b) are aspreviously disclosed, and an activated carboxylic acid or chloroformate10-3, wherein A is an activating group, and X⁵ is disclosed above, witha base, such as triethylamine, diisopropylethylamine,4-methylmorpholine, 4-dimethylaminopyridine, or pyridine, in ananhydrous aprotic solvent such as dichloromethane, tetrahydrofuran,1,2-dichloroethane, N,N-dimethylformamide, or any combination thereof,at temperatures between about 0° C. and about 120° C. (Scheme 10, stepb).

Activated carboxylic acids 10-3 may be an acid halide, such as an acidchloride, an acid bromide, or an acid fluoride; a carboxylic ester, suchas a p-nitrophenyl ester, a pentafluorophenyl ester, an ethyl(hydroxyimino)cyanoacetate ester, a methyl ester, an ethyl ester, abenzyl ester, an N-hydroxysuccinimidyl ester, a hydroxybenzotriazol-1-ylester, or a hydroxypyridyltriazol-1-yl ester; an O-acylisourea; an acidanhydride; or a thioester. Acid chlorides may be prepared from thecorresponding carboxylic acids by treatment with a dehydratingchlorinating reagent, such as oxalyl chloride or thionyl chloride.Activated carboxylic esters 10-3 may be prepared from carboxylic acidsin situ with a uronium salt, such as1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU),O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate(HBTU), or(1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbeniumhexafluorophosphate (COMU). Activated carboxylic esters 10-3 may also beprepared from carboxylic acids in situ with a phosphonium salt such asbenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate(PyBop). Activated carboxylic esters 10-3 may also be prepared fromcarboxylic acids in situ with a coupling reagent, such as1-(3-dimethylamino propyl)-3-ethylcarbodiimide ordicyclohexylcarbodiimide, in the presence of a triazole such ashydroxybenzotriazole.monohydrate (HOBt) or 1-hydroxy-7-azabenzotriazole(HOAt). O-Acylisoureas may be prepared with a dehydrating carbodimidesuch as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide ordicyclohexylcarbodiimide. Activated carboxylic esters 10-3 may also beprepared from carboxylic acids in situ with a coupling reagent such as2-chloro-1,3-dimethylimidazolidinium hexafluorophosphate (CIP) in thepresence of a triazolol such as 1-hydroxy-7-azabenzotriazole (HOAt).Activated carboxylic esters 10-3 may also be prepared from carboxylicacids in situ with a coupling reagent such as2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®)in the presence of a base such as pyridine.

Cyclopropyl amides 10-6, wherein Q² is O, and R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R^(17a), and R^(17b) are aspreviously disclosed, and X⁵ is N(R^(17a))(C₁-C₈)alkyl,N(R^(17a))(C₁-C₈)haloalkyl, N(R^(17a))(C₃-C₈)cycloalkyl, and N(R^(17a))(substituted and unsubstituted phenyl), may be prepared by treatment ofcyclopropyl amides 10-2, wherein Q² is O, and R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R^(17a), and R^(17b) are aspreviously disclosed, with an isocyanate or isothiocyanate 10-5, whereinQ⁴ is O or S, respectively, and X⁵ is as disclosed above, in ananhydrous solvent such as tetrahydrofuran or ethanol, at temperaturesbetween about 0° C. and about 80° C. (Scheme 10, step c).

Cyclopropyl amides 10-7, wherein Q² is O, R^(17b) is H, R^(17c) issubstituted or unsubstituted heterocyclyl, substituted or unsubstituted(C₁-C₈)alkyl, and (C₃-C₆)cycloalkyl, and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸,R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R^(17a) are as previouslydisclosed, may be prepared by treatment of cyclopropyl amides 10-2wherein Q² is O, R^(17b) is H, and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹,Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ are as previously disclosed, with analdehyde of ketone, wherein R^(17c) is as disclosed above, in thepresence of an acid, such as acetic acid, and a reducing agent, such assodium cyanoborohydride, in a polar aprotic solvent, such as ethanol, attemperatures between about 0° C. C and about 80° C. (Scheme 10, step b).

Cyclopropyl amides 11-3, wherein Q² is O, and R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R^(18a), R^(18b), R^(18c) areas previously disclosed, may be prepared by treatment of hydrazide 11-1wherein Q² is O, and R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Q¹, R¹⁰, R¹¹,R¹², R¹³, R¹⁴, and R^(18a) are as previously disclosed, with aldehydesor ketones 11-2, wherein R^(18b) and R^(18c) are as previouslydisclosed, with or without an acid, such as acetic acid, in a polaraprotic solvent such as ethanol, at temperatures between about 0° C. andabout 80° C. (Scheme 18, step a).

In some embodiments, 1-3 may be prepared from the α,β-unsaturatedaldehyde 12-1, wherein R¹, R², R³, R⁴, R⁵, R⁶, and R⁹ are as previously.It will be understood by one skilled in the art that compound 12-1 maybe synthesized via Aldol condensation (see Yoshikawa, M.; Kamei, T. PCTInt. Appl. 2010123006, 2010) of an appropriately substituted,commercially available aldehyde and acetaldehyde. Treatment of 12-1 witha (C₁-C₆)alkyl orthoformate, in the presence of an acid whose pH is 0-5such as hydrobromic acid, N-bromosuccinimide, hydrochloric acid,N-chlorosuccinimide, and pyridinium p-toluenesulfonate (PPTS), in a(C₁-C₆)alkanol solvent, at a temperature from 0° C. to ambient and underambient pressure provides the acetal 12-2, wherein R¹, R², R³, R⁴, R⁵,R⁶, and R⁹ are as previously disclosed and R^(a) is a (C₁-C₆)alkyl orR^(a) and R^(a) taken together can form a cyclic acetal (Scheme 12, stepa). The acetal 12-2 may be converted to the cyclopropyl acetal 12-3,wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, and R^(a) are as previouslydisclosed, by treatment with a carbene source such as a haloform, forexample, bromoform or chloroform, in the presence of an inorganic base,such as sodium or potassium hydroxide or sodium or potassium carbonate,and a phase-transfer catalyst such as benzyl triethylammonium chloride,(−)-N-dodecyl-N-methylephedrinium bromide, tetramethylammonium bromide,tetrapropylammonium bromide, tetrabutylammonium tetrafluoroborate,tetramethylammonium chloride or tetrabutylammonium hexafluorophosphateat a temperature from about ambient temperature up to below the boilingpoint of the haloform (Scheme 12, step b). Caution: Step B is anexothermic reaction and careful control of the exotherm should beexercised when conducting this reaction. The cyclopropyl acetal 12-3 maybe transformed into the aldehyde 12-4, wherein R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, and R⁹ are as previously disclosed, in a polar solvent selectedfrom the group consisting of acetone, acetonitrile, methanol, ethanol,nitromethane, N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate,tetrahydrofuran and 1,4-dioxane, in the presence of an aqueous mineralacid selected from the group consisting of nitric acid, hydrochloricacid, hydrobromic acid, and sulfuric acid (Scheme 12, step c) at ambienttemperature. The cyclopropyl acid 1-3, wherein R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, and R⁹ are as previously disclosed, may be obtained by oxidationof the aldehyde 12-4 with oxidants such sodium permanganate or potassiumpermanganate, or under Pinnick oxidation conditions in a polar aproticsolvent selected from the group consisting of acetone, acetonitrile,N,N-dimethylformamide, dimethyl sulfoxide, ethyl acetate,tetrahydrofuran and 1,4-dioxane at a temperature from about 0° C. toabout ambient temperature (Scheme 12, step d). Standard safetyprecautions should be exercised because an exotherm may occur whenconducting this reaction.

It will be understood by those skilled in the art that, in someembodiments, the cyclopropyl acid 1-3, wherein R¹, R², R³, R⁴, R⁵, R⁶,R⁷, R⁸, and R⁹ are as previously disclosed, may be resolved into its(R,R) and (S,S) enantiomers via a method such as that in Kovalenko V.N., Kulinkovich O. G. Tetrahedron: Asymmetry 2011, 22, 26 (Scheme 13,step a).

In another embodiment, the cyclopropyl acid R1-3, wherein R¹, R², R³,R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ are as previously disclosed, may be resolvedinto its (R,R) and (S,S) enantiomers via a method in Scheme R!.

wherein: X^(R) is selected from the group consisting of C₁-C₄ alkyl orbenzyl.

In Scheme R1, the (±)-trans-racemate of Formula R1-1 (i.e., the mixtureof (R,R) and (S,S) enantiomers of a trans-2,2-dichloro-3-(substitutedphenyl)cyclopropane-carboxylic acid) is combined with a resolving agentthat is either the enantiomeric amine of Formula R2-1 or Formula R2-2,in a suitable solvent, to provide the diastereomeric amine salts ofFormula R3-1A or Formula R3-1B,

or of Formula R3-2A or Formula R3-2B,

that selectively crystallize or precipitate out of the resultingmixture. The diastereomeric amine salt of Formula R3-1A or FormulaR3-1B, or of Formula R3-2A or Formula R3-2B, can then be isolated fromthe mixture and treated with an acid to provide the (1R,3R)- or the(1S,3S)-2,2-dihalo-3-(substituted phenyl)cyclopropanecarboxylic acid ofFormula R1-2A or Formula R1-2B, respectively.

EXAMPLES

These examples are for illustration purposes and are not to be construedas limiting this disclosure to only the embodiments disclosed in theseexamples.

Starting materials, reagents, and solvents that were obtained fromcommercial sources were used without further purification. Anhydroussolvents were purchased as Sure/Seal™ from Aldrich and were used asreceived. Melting points were obtained on a Thomas Hoover Unimeltcapillary melting point apparatus or an OptiMelt Automated Melting PointSystem from Stanford Research Systems and are uncorrected. Examplesusing “room temperature” were conducted in climate controlledlaboratories with temperatures ranging from about 20° C. to about 24° C.Molecules are given their known names, named according to namingprograms within ISIS Draw, ChemDraw, or ACD Name Pro. If such programsare unable to name a molecule, such molecule is named using conventionalnaming rules. ¹H NMR spectral data are in ppm (δ) and were recorded at300, 400, 500, or 600 MHz; ¹³C NMR spectral data are in ppm (δ) and wererecorded at 75, 100, or 150 MHz; and ¹⁹F NMR spectral data are in ppm(δ) and were recorded at 376 MHz, unless otherwise stated.

Example 1 Preparation oftrans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-methyl-4-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1061)

To a solution oftrans-N-(4-amino-2-methylphenyl)-2-chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(DP1) (0.100 g, 0.179 mmol) and triethylamine (0.037 mL, 0.269 mmol) indichloromethane (2.0 mL) was added trifluoroacetic anhydride (0.030 mL,0.215 mmol). The reaction mixture was stirred at room temperature for 18hours. The reaction mixture was directly loaded onto a Celite®cartridge. Purification by flash column chromatography using 0-40% ethylacetate/hexanes as eluent afforded the title compound as a white solid(0.080 g, 68%).

The following compounds were prepared in like manner to the procedureoutlined in Example 1:

trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-(2,2-difluoroacetamido)-2-methylphenyl)benzamide(F1062)

Isolated as a white solid (0.109 g, 95%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1064)

Isolated as a light yellow solid (0.103 g, 89%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1065)

Isolated as a white solid (0.088 g, 77%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3,5-difluoro-4-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1120)

Isolated as an off-white solid (0.096 g, 82%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-fluoro-2-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1121)

Isolated as a light yellow solid (0.111 g, 85%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-(2,2-difluoroacetamido)-3,5-difluorophenyl)benzamide(F1122)

Isolated as an off-white solid (0.066 g, 58%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-(2,2-difluoroacetamido)-4-fluorophenyl)benzamide(F1123)

Isolated as an off-white solid (0.0885 g, 74%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-4-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1261)

Isolated as a light yellow foam (0.065 g, 69%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-3-fluorobenzamide(F1330)

Isolated as a white powder (0.068 g, 98%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-3-fluorobenzamide(F1333)

Isolated as an off-white powder (0.069 g, 100%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-3-fluorobenzamide(F1334)

Isolated as an off-white powder (0.062 g, 100%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-3-fluorobenzamide(F1335)

Isolated as a light yellow powder (0.057 g, 99%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3,5-difluoro-4-(2,2,2-trichloroacetamido)phenyl)benzamide(F1146)

Isolated as an off-white solid (0.046 g, 37%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-3-fluorobenzamide(F1256)

Isolated as a light tan foam (0.184 g, 56%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-3-fluorobenzamide(F1287)

Isolated as a white solid (0.064 g, 90%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-3-fluorobenzamide(F1288)

Isolated as a white solid (0.068 g, 93%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)-cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-3-fluorobenzamide(F1289)

Isolated as a white solid (0.065 g, 91%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-3-fluorobenzamide(F1290)

Isolated as a white solid (0.068 g, 93%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-3-fluorobenzamide(F1291)

Isolated as a white solid (0.062 g, 95%).

Example 2 Preparation ofN-(3-acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1083)

To a solution ofN-(3-amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(DP2) (0.06 g, 0.104 mmol) in pyridine (0.30 mL, 3.71 mmol) stirred atroom temperature was added acetic anhydride (9.77 μl, 0.104 mmol). Thereaction mixture was stirred at room temperature for 18 hours, wasquenched with water (3 mL), and was extracted with ethyl acetate (10mL). The organic layer was washed with hydrochloric acid (1 N) and brinebefore being poured through a phase separator. The organic layer wasconcentrated under reduced pressure to give a residue. Purification bycolumn chromatography using 0-30% ethyl acetate/hexanes as eluentafforded the title compound as a white solid (0.043 g, 67%).

The following compounds were prepared in like manner to the procedureoutlined in Example 2:

2-Chloro-N-(3-(2-chloro-2,2-difluoroacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1248)

Isolated as a white solid (0.089 g, 74%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,3,3,3-pentafluoropropanamido)phenyl)benzamide(F1251)

Isolated as a white solid (0.072 g, 57%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-dichloroacetamido)-2,4-difluorophenyl)benzamide(F1252)

Isolated as a white solid (0.068 g, 57%).

N-(4-Acetamido-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1262)

Isolated as a white solid (0.022 g, 26%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-(2,2-dichloroacetamido)-2,6-difluorophenyl)benzamide(F1272)

Isolated as a white solid (0.028 g, 29%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)benzamide(F1234)

Isolated as a white foamy solid (0.083 g, 66%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)benzamide(F1238)

Isolated as an off-white foamy solid (0.090 g, 72%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)benzamide(F1240)

Isolated as a white foamy solid (0.100 g, 84%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)benzamide(F1241)

Isolated as a white foamy solid (0.086 g, 68%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1242)

Isolated as a glassy solid (0.074 g, 59%).

2-Chloro-N-(5-(2-chloro-2,2-difluoroacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1243)

Isolated as a white foamy solid (0.065 g, 49%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-dichloroacetamido)-2,4-difluorophenyl)benzamide(F1244)

Isolated as an off-white foamy solid (0.035 g, 28%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1245)

Isolated as a white foamy solid (0.080 g, 65%).

N-(5-Acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1246)

Isolated as an off-white foamy solid (0.080 g, 71%).

trans-N-(4-Acetamido-3,5-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1124)

Isolated as an off-white solid (0.042 g, 39%).

trans-N-(2-Acetamido-4-fluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1125)

Isolated as an off-white solid (0.039 g, 33%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-fluoro-2-(2,2,2-trichloroacetamido)phenyl)benzamide(F1126)

Isolated as a light yellow solid (0.078 g, 59%).

Example 3 Preparation of2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1169)

Trifluoroacetic anhydride (0.035 g, 0.251 mmol) was added dropwise to astirred solution ofN-(3-amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(DP9) (0.100 g, 168 mmol), and triethylamine (0.051 g, 0.503 mmol) inanhydrous dichloromethane (3 mL). The solution was stirred for 12 hoursat 23° C. and concentrated. Purification by silica gel flashchromatography gave the title compound as a white foam (0.084 g, 69%).

The following compounds were prepared in like manner to the procedureoutlined in Example 3:

2-Chloro-N-(3-(2-chloro-2,2-difluoroacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1170)

Isolated as a white solid (0.089 g, 71%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-dichloroacetamido)-2,4-difluorophenyl)benzamide(F1174)

Isolated as a white foam (0.058 g, 46%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1175)

Isolated as a white solid (0.283 g, 70%).

N-(3-Benzamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1179)

Isolated as a white foam (0.015 g, 12%).

N-(3-(2-Bromo-2,2-difluoroacetamido)-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1276)

Isolated as a white solid (0.078 g, 59%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1331)

Isolated as a white foam (0.037 g, 62%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1332)

Isolated as a white solid (0.031 g, 51%).

Example 4 Preparation oftert-butyl(4-((3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)amino)-4-oxobutyl)carbamate(F1199)

To a solution ofN-(3-amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(DP2) (0.100 g, 0.173 mmol) in ethyl acetate (2 mL) stirred at roomtemperature were added 4-((tert-butoxycarbonyl)amino)butanoic acid(0.035 g, 0.173 mmol) and pyridine (0.028 mL, 0.345 mmol).2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®;165 mg, 0.259 mmol) was added a 50% solution in ethyl acetate. Thereaction mixture was warmed to 50° C. for 18 hours then cooled to roomtemperature and concentrated under a stream of nitrogen. Purification bycolumn chromatography using 0-80% ethyl acetate/hexanes as eluentafforded the title compound as a white solid (0.111 g, 84%).

The following compounds were prepared in like manner to the procedureoutlined in Example 4:

trans-tert-Butyl(4-((4-(2-chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)-cyclopropane-1-carboxamido)benzamido)-3-methylphenyl)amino)-4-oxobutyl)carbamate(F1200)

Isolated as a white solid (0.097 g, 72%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoropropanamido)-2,4-difluorophenyl)benzamide(F1249)

Isolated as a white solid (0.097 g, 83%).

N-(3-Benzamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1253)

Isolated as a light brown solid (0.076 g, 64%).

Example 5 Preparation oftrans-N-(3-acetamido-2-chloro-4-fluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1160)

2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®,50% solution in ethyl acetate; 0.281 g, 0.441 mmol) was added dropwiseto a stirred solution oftrans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoicacid (C12) (0.100 g, 220 mmol),N-(3-amino-2-chloro-6-fluorophenyl)acetamide (C194) (0.048 g, 0.220mmol), and pyridine (0.053 g, 0.661 mmol) in anhydrous ethyl acetate (3mL). The solution was stirred for 12 hours at 23° C. and concentrated.Purification by silica gel flash chromatography gave the title compoundas a white foam (0.105 g, 71%).

The following compounds were prepared in like manner to the procedureoutlined in Example 5:

N-(3-Acetamido-2-chloro-4-fluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1161)

Isolated as a white foam (0.052 g, 71%).

Example 6 Preparation of2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(4-fluorobenzamido)phenyl)benzamide(F1204)

2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®,50% solution in ethyl acetate; 0.213 g, 0.335 mmol) was added dropwiseto a stirred solution ofN-(3-amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(DP9) (0.100 g, 0.168 mmol), 4-fluorobenzoic acid (0.028 g, 0.201 mmol),and pyridine (0.040 g, 0.503 mmol) in anhydrous ethyl acetate (3 mL).The solution was stirred for 12 hours at 50° C. and concentrated.Purification by silica gel flash chromatography gave the title compoundas a white foam (0.029 g, 23%).

The following compounds were prepared in like manner to the procedureoutlined in Example 6:

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(4-methoxybenzamido)phenyl)benzamide(F1205)

Isolated as a white solid (0.020 g, 16%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)nicotinamide(F1206)

Isolated as a white solid (0.041 g, 33%).

N-(3-Acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1231)

Isolated as a white solid (0.029 g, 26%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)-6-fluoronicotinamide(F1258)

Isolated as a white solid (0.019 g, 15%).

2-Chloro-N-(3-(1-cyanocyclopropane-1-carboxamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1263)

Isolated as a white foam (0.078 g, 64%).

2-Chloro-N-(3-(cyclopropanecarboxamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1264)

Isolated as a white foam (0.100 g, 85%).

2-Chloro-N-(3-(2,2-dichloro-1-methylcyclopropane-1-carboxamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1273)

Isolated as a white solid (0.078 g, 30%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-pivalamidophenyl)benzamide(F1274)

Isolated as a white solid (0.014 g, 12%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluorocyclopropane-1-carboxamido)-2,4-difluorophenyl)benzamide(F1275)

Isolated as a white solid (0.135 g, 73%).

2-Chloro-N-(3-(cyclohex-3-ene-1-carboxamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1297)

Isolated as a white solid (0.119 g, 96%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-oxo-2-phenylacetamido)phenyl)benzamide(F1298)

Isolated as a clear colorless oil (0.087 g, 68%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(methylsulfonyl)acetamido)phenyl)benzamide(F1299)

Isolated as a white foam (0.111 g, 88%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)furan-2-carboxamide(F1300)

Isolated as a white solid (0.085 g, 70%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,3,3-tetrafluoropropanamido)phenyl)benzamide(F1301)

Isolated as a white foam (0.103 g, 81%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)-5-methylthiophene-2-carboxamide(F1302)

Isolated as a white solid (0.035 g, 28%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(3-oxocyclobutane-1-carboxamido)phenyl)benzamide(F1303)

Isolated as a white solid (0.093 g, 76%).

Example 7 Preparation oftrans-N-(4-Acetamido-2-methylphenyl)-2-chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1059)

To a solution oftrans-N-(4-amino-2-methylphenyl)-2-chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(DP1) (0.100 g, 0.179 mmol) and triethylamine (0.037 mL, 0.269 mmol) indichloromethane (2.0 mL) was added acetyl chloride (0.015 g, 0.197mmol). The reaction mixture was stirred at room temperature for 18hours. The reaction mixture was diluted with ethyl acetate and washedwith hydrochloric acid (1 N; 2×) and brine. Celite® was added to theorganic layer, and the mixture was concentrated under reduced pressure.Purification by flash column chromatography using 0-40% ethylacetate/hexanes as eluent afforded the title compound as an off-whitesolid (0.079 g, 73%).

The following compounds were prepared in like manner to the procedureoutlined in Example 7:

trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-methyl-4-(2,2,2-trichloroacetamido)phenyl)benzamide(F1060)

Isolated as a white solid (0.060 g, 47%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trichloroacetamido)phenyl)benzamide(F1063)

Isolated as a white solid (0.039 g, 34%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-methoxyacetamido)phenyl)benzamide(F1254)

Isolated as a white solid (0.072 g, 64%).

Example 8 Preparation of2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(N-(methylsulfonyl)methylsulfonamido)phenyl)benzamide(F1277)

Methanesulfonyl chloride (0.029 g, 0.251 mmol) was added dropwise to astirred solution ofN-(3-amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(DP9) (0.100 g, 168 mmol) and triethylamine (0.051 g, 0.503 mmol) inanhydrous dichloromethane (3 mL). The solution was stirred for 12 hoursat 23° C. and concentrated. Purification by silica gel flashchromatography gave the title compound as a white foam (0.044 g, 33%).

Example 9 Preparation of2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(phenylsulfonamido)phenyl)benzamide(F1295)

Benzenesulfonyl chloride (0.044 g, 0.251 mmol) was added to a stirredsolution ofN-(3-amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(DP9) (0.100 g, 168 mmol) in acetonitrile (3 mL). The solution wasstirred for 36 hours at 70° C. and concentrated. Purification by silicagel flash chromatography provided the title compound as a pink solid(0.112 g, 86%).

Example 10 Preparation oftrans-2-chloro-N-(4-((4-chlorobenzyl)amino)-2-methylphenyl)-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1010)

4-Chlorobenzaldehyde (0.0252 g, 0.179 mmol) was added to a stirredsuspension oftrans-N-(4-amino-2-methylphenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(DP4) (0.100 g, 0.179 mmol) and sodium acetate (29.4 mg, 0.359 mmol) inmethanol (20 mL), water (15 mL) and acetic acid (3 mL). The resultingheterogeneous mixture was stirred at 25° C. for 3 hours. Sodiumcyanoborohydride (0.0158 g, 0.251 mmol) was added in one portion. Theresulting colorless solution was stirred at ambient temperature foranother 4 hours. The reaction mixture was quenched with water (50 mL)and extracted with diethyl ether (3×50 mL). The organic extracts werewashed successively with water and saturated aqueous sodium chloridesolution, dried over anhydrous magnesium sulfate, and concentrated undervacuum on a rotary evaporator. Purification by silica gel flashchromatography provided the title compound as a yellow foam (0.087 g,68%).

The following compounds were prepared in like manner to the procedureoutlined in Example 10:

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-((4-methoxybenzyl)amino)-2-methylphenyl)benzamide(F1035)

Isolated as a yellow foam (0.095 g, 74%).

trans-2-Chloro-N-(4-((4-cyanobenzyl)amino)-2-methylphenyl)-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1040)

Isolated as a yellow solid (0.097 g, 76%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-methyl-4-((4-methylbenzyl)amino)phenyl)benzamide(F1041)

Isolated as a yellow solid (0.081 g, 65%).

trans-2-Chloro-5-(2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-((4-methoxybenzyl)amino)phenyl)benzamide(F1096)

Isolated as a white foam (0.059 g, 47%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-methyl-4-((4-(trifluoromethoxy)benzyl)amino)phenyl)benzamide(F1117)

Isolated as a yellow solid (0.113 g, 82%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-methyl-4-((4-nitrobenzyl)amino)phenyl)benzamide(F1166)

Isolated as a yellow oil (0.076 g, 77%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-methyl-4-((4-(trifluoromethyl)benzyl)amino)phenyl)benzamide(F1165)

Isolated as a pale yellow solid (0.055 g, 54%).

trans-N-(4-(Benzylamino)-2-methylphenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1176)

Isolated as a pale yellow foam (0.039 g, 42%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-methyl-4-(phenethylamino)phenyl)benzamide(F1177)

Isolated as a pale yellow foam (0.025 g, 27%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-methyl-4-((2-phenylpropyl)amino)phenyl)benzamide(F1178)

Isolated as a pale yellow foam (0.055 g, 58%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-((4-nitrobenzyl)amino)phenyl)benzamide(F1296)

Isolated as a yellow oil (0.008 g, 4%).

Example 11 Preparation oftrans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-fluoro-3-vinylphenyl)benzamide(F1311)

To a solution oftrans-N-(3-bromo-4-fluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1304) (0.4 g, 0.64 mmol) in 1,4-dioxane (7 mL) degassed with argonwere added tributylvinyltin (0.26 mL, 0.89 mmol) andbis(triphenylphosphine)palladium(II) dichloride (0.044 g, 0.064 mmol),and the reaction mixture was irradiated in a microwave at 90° C. for 1hours. The reaction mixture was cooled to room temperature, diluted withwater and extracted with ethyl acetate (2×10 mL). The organic layer wasdried over anhydrous sodium sulfate, filtered and concentrated underreduced pressure. Purification by column chromatography using 15-20%ethyl acetate/petroleum ether as eluent afforded the title compound asan off-white solid (0.11 g, 40%).

The following compounds were prepared in like manner to the procedureoutlined in Example 11:

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-fluoro-2-vinylphenyl)benzamide(F1312)

Isolated as an off-white solid (0.12 g, 44%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-fluoro-4-vinylphenyl)benzamide(F1313)

Isolated as an off-white solid (0.18 g, 49%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-vinylphenyl)benzamide(F1314)

Isolated as an off-white solid (0.07 g, 26%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-vinylphenyl)benzamide(F1315)

Isolated as an off-white solid (0.13 g, 48%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-6-vinylphenyl)benzamide(F1316)

Isolated as an off-white solid (0.12 g, 44%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3,4-difluoro-5-vinylphenyl)benzamide(F1317)

Isolated as an off-white solid (0.10 g, 37%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-fluoro-3-(1-fluorovinyl)phenyl)benzamide(F1318)

Isolated as an off-white solid (0.15 g, 55%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-fluoro-2-(1-fluorovinyl)phenyl)benzamide(F1319)

Isolated as an off-white solid (0.17 g, 70%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-fluoro-4-(1-fluorovinyl)phenyl)benzamide(F1320)

Isolated as an off-white solid (0.15 g, 62%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(1-fluorovinyl)phenyl)benzamide(F1321)

Isolated as an off-white solid (0.12 g, 63%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-6-(1-fluorovinyl)phenyl)benzamide(F1322)

Isolated as an off-white solid (0.09 g, 50%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3,4-difluoro-5-(1-fluorovinyl)phenyl)benzamide(F1323)

Isolated as an off-white solid (0.11 g, 58%).

Example 12 Preparation oftrans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-((2-hydroxyethyl)amino)-2-methylphenyl)benzamide(F1130)

4 M Hydrogen chloride in 1,4-dioxane (0.370 mL, 1.479 mmol) was addeddropwise to a stirred solution oftrans-2-((tert-butoxycarbonyl)(4-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-3-methylphenyl)amino)ethylacetate (F1129) (0.110 g, 0.148 mmol) in dichloromethane (5 mL). Theresulting suspension of solid was stirred for 12 hours at 23° C. andthen quenched with saturated aqueous sodium bicarbonate (5 mL). Theaqueous mixture was extracted with ethyl acetate (3×5 mL) and theorganic extract was washed with saturated aqueous sodium chloridesolution (5 mL) and concentrated under vacuum on a rotary evaporator.Purification by silica gel flash chromatography gave the title compoundas a pale yellow foam (0.050 g, 53%).

The following compounds were prepared in like manner to the procedureoutlined in Example 12:

2-((4-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-3-methylphenyl)amino)ethylacetate (F1144)

Isolated as a clear colorless oil (0.043 g, 31%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(4-((2-hydroxyethyl)amino)-2-methylphenyl)benzamide(F1145)

Isolated as a pale yellow foam (0.040 g, 31%).

trans-N-(4-((3-Amino-3-oxopropyl)amino)-2-methylphenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1158)

Isolated as a grey solid (0.013 g, 16%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-((2-methoxyethyl)amino)-2-methylphenyl)benzamide(F1162)

Isolated as a pale yellow foam (0.062 g, 86%).

Example 13 Preparation ofN-(3-amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1255)

To a solution oftert-butyl-N-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-carbonyl]amino]-3-fluorobenzoyl]amino]-2,6-difluorophenyl]carbamate(F1239) (0.166 g, 0.21 mmol) in dioxane (1 mL) was added a 4 molarsolution of hydrogen chloride in dioxane (0.53 mL, 2.12 mmol), and thecolorless solution was stirred at room temperature for 16 hours. Thelight-yellow solution was concentrated and the residue was partitionedbetween ethyl acetate (5 mL) and saturated aqueous sodium bicarbonate (5mL). The phases were separated and the aqueous phase was extracted withadditional ethyl acetate (2×2.5 mL). The combined organic extracts werewashed with brine (3 mL), dried over sodium sulfate, filtered, andconcentrated to an amber residue. The residue was dissolved in minimalethyl acetate and adsorbed to Celite®. Purification by automated flashchromatography using a gradient of 0-40% ethyl acetate in hexanes aseluent provided the title compound as a white solid (0.111 g, 88%).

The following compounds were prepared in like manner to the procedureoutlined in Example 13:

N-(3-Amino-2,4-difluorophenyl)-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluoro-3-methylbenzamide(F1151)

Isolated as a white solid (0.056 g, 74%).

N-(3-(4-Aminobutanamido)-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1201)

Isolated as a white foam (0.077 g, 81%).

trans-N-(4-(4-Aminobutanamido)-2-methylphenyl)-2-chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1202)

Isolated as a white solid (0.035 g, 42%).

N-(3-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1227)

Isolated as a brown foamy solid (0.225 g, 95%).

N-(3-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1228)

Isolated as an off-white foam (0.216 g, 97%).

N-(3-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1247)

Isolated as a white foamy solid (0.195 g, 92%).

N-(3-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1250)

Isolated as a white foamy solid (0.225 g, 97%).

N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-methylbenzamide(F1056)

Isolated as a beige foam (0.1 g, 85%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(3-(3,5-dichlorophenyl)-2,2-difluorocyclopropane-1-carboxamido)benzamide(F1080)

Isolated as an off-white powder (0.94 g, 94%).

N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1324)

Isolated as a light yellow solid (0.195 g, 75%).

N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1325)

Isolated as an off-white solid (0.130 g, 46%).

N-(3-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1336)

Isolated as a tan powder (0.160 g, 81%).

trans-N-(3-Amino-2,4-difluorophenyl)-2,6-dichloro-3-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1110)

Isolated as a light-tan solid (0.034 g, 76%).

trans-N-(3-Amino-2,4-difluorophenyl)-3-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,6-difluorobenzamide(F1111)

Isolated as a tan solid (0.044 g, 80%).

trans-N-(4-Amino-3,5-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(DP3)

Isolated as a light brown foam (1.59 g, 93%).

trans-N-(3-Amino-2,4-difluorophenyl)-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluoro-3-methylbenzamide(F1151)

Isolated as a white solid (0.056 g, 74%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1156)

Isolated as a tan solid (0.100 g, 86%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1222)

Isolated as a tan solid (0.054 g, 46%).

trans-N-(3-Amino-2,4-difluorophenyl)-3-chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-methylbenzamide(F1223)

Isolated as a tan foam (0.052 g, 46%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-(trifluoromethyl)benzamide(F1225)

Isolated as a white solid (0.052 g, 83%).

trans-N-(3-Amino-2,4-difluorophenyl)-5-(2,2-dichloro-3-(3-chloro-4-fluoro-phenyl)cyclopropane-1-carboxamido)-3-fluoro-2-methoxybenzamide(F1226)

Isolated as a white solid (0.053 g, 81%).

N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1284)

Isolated as a white solid (0.193 g, 91%).

N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1285)

Isolated as a white solid (0.208 g, 93%).

trans-N-(3-Amino-2,4-difluorophenyl)-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluoro-2-methylbenzamide(F1286)

Isolated as a white solid (0.062 g, 89%).

trans-N-(4-Amino-2-methylphenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(DP4)

Isolated as a white solid (0.053 g, 83%).

N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(DP2)

Isolated as a white solid (0.115 g, 89%).

N-(5-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(DP5)

Isolated as a white solid (0.107 g, 96%).

Example 14 Preparation oftrans-N-(2-amino-4-fluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(DP6)

To a slurry oftrans-2-chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-fluoro-2-nitrophenyl)benzamide(DP13) (0.880 g, 1.49 mmol) in a 4:1 mixture of methanol (14 mL) andwater (4.7 mL) were added iron powder (0.415 g, 7.44 mmol) and ammoniumchloride (0.239 g, 4.46 mmol), and the mixture was warmed to 55° C. andstirred for 21 hours. The reaction mixture was filtered through a pad ofCelite®, washing with ethyl acetate. The filtrate was concentrated underreduced pressure, and the residue was partitioned between ethyl acetate(100 mL) and water (60 mL). The phases were separated and the organicphase was dried over magnesium sulfate, filtered, and concentrated togive a dark residue. The residue was dissolved in minimal ethyl acetateand adsorbed to Celite®. Purification by automated flash chromatographyusing a gradient of 0-40% ethyl acetate in hexanes as eluent gave thetitle compound as a yellow foam (0.66 g, 75%).

The following compounds were prepared in like manner to the procedureoutlined in Example 14:

N-(2-Amino-3-fluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1133)

Isolated as a light brown powder (0.030 g, 80%).

N-(2-Amino-4,5-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1134)

Isolated as a light brown film (0.016 g, 34%).

N-(5-Amino-2-fluoro-4-methylphenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1135)

Isolated as a light blue solid (0.050 g, 59%).

Example 15 Preparation oftrans-N-(4-amino-2,3-dimethylphenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1229)

Iron powder (325 mesh; 0.065 g, 1.163 mmol) was added to a stirredsolution of ethanol (10 mL) and concentrated HCl (0.01 mL, 0.116 mmol).The suspension was heated at 65° C. for 1 hour and then cooled to 55° C.A solution of ammonium chloride (0.045 g, 0.838 mmol) in water (3 mL)was added, followed bytrans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,3-dimethyl-4-nitrophenyl)benzamide(F1180) (0.140 g, 0.233 mmol). The reaction mixture was heated to 60° C.for 2 hours, cooled, and filtered through a pad of Celite®. The filtratewas extracted with ethyl acetate (3×20 mL). The combined organicextracts were washed with water and brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated under reduced pressure ona rotary evaporator. Purification of the crude product by silica gelflash chromatography afforded the title compound as a tan solid (0.032g, 23%)

The following compounds were prepared in like manner to the procedureoutlined in Example 15:

trans-N-(4-Amino-2,5-dimethylphenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1257)

Isolated as a gold foam (0.047 g, 36%).

Example 16 Preparation oftrans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-hydroxyphenyl)benzamide(F1203)

trans-3-(2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenylacetate (F1193) (0.067 g, 0.108 mmol) was dissolved in methanol (2.2 mL)and treated with saturated sodium hydrogen carbonate solution (0.5 mL)with stirring at room temperature. Analysis of the reaction mixtureafter 1 hour by thin layer chromatography (2:1 hexanes-ethyl acetate)indicated that the reaction was complete. The reaction mixture waspartitioned between ethyl acetate and 1N aqueous hydrochloric acid, thelayers were separated, and the organic layer was dried over sodiumsulfate. Purification by preparative thin layer chromatography(20×20×0.2 cm plate, 3:1 hexanes-ethyl acetate) gave the title compoundas a tan foam (0.06 g, 96%).

Example 17 Preparation oftert-butyl-N-tert-butoxycarbonyl-N-[3-[2-chloro-[5-[[(1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarbonyl]amino]-3-fluorobenzoyl]amino]-2,6-difluorophenyl]carbamate(F1292)

(1R,3R)-2,2-Dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylicacid (C91) (0.131 g, 0.436 mmol) as a slurry in toluene (4 mL) wastreated with oxalyl chloride (0.382 mL. 4.36 mmol) and a single drop ofN,N-dimethyl formamide with stirring at room temperature. After themixture became homogeneous and gas evolution ceased, the solution wasconcentrated to a clear oil.tert-Butyl-N-tert-butoxycarbonyl-N-(3-(5-amino-2-chloro-3-fluorobenzamido)-2,6-difluorophenyl)carbamate(C108) (0.225 g, 0.436 mmol) and sodium bicarbonate (0.110 g, 1.31 mmol)were added to the flask as solids followed by ethyl acetate (4 mL), andthe cloudy mixture was allowed to stir at room temperature for 18 hours.Analysis of an aliquot by liquid chromatography/mass spectroscopyindicated complete conversion to the desired compound. The reactionmixture was partitioned between ethyl acetate and an aqueous mixture ofsodium hydrogen carbonate and sodium chloride. The layers were separatedand the organic layer was dried over sodium sulfate, filtered andconcentrated to an oil. Trituration with hexanes and drying yielded thetitle compound as an off-white solid (0.347 g, 100%).

The following compounds were prepared in like manner to the procedureoutlined in Example 17:

tert-Butyl-N-tert-butoxycarbonyl-N-(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamido)-2,6-difluorophenyl)carbamate(F1294)

Isolated as an off-white solid (0.367 g, 100%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamido)-2,6-difluorophenyl)carbamate(F1326)

Isolated as a yellow glass (0.257 g, 100%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamido)-2,4-difluorophenyl)carbamate(F1327)

Isolated as a yellow glass (0.240 g, 99%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamido)-2,4-difluorophenyl)carbamate(F1328)

Isolated as a yellow glass (0.245 g, 100%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-3-fluorobenzamido)-2,4-difluorophenyl)carbamate(F1329)

Isolated as a light yellow glass (0.242 g, 100%).

Example 18 Preparation oftrans-5-(3-(3-bromo-4,5-dichlorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(4-fluorophenyl)benzamide(F1005)

Dichloromethane (2 mL) was added to a 20 mL glass vial containing5-amino-2-chloro-N-(4-fluorophenyl)benzamide (C98) (0.105 g, 0.396mmol), 4-dimethylaminopyridine (0.053 g, 0.436 mmol),trans-3-(3-bromo-4,5-dichlorophenyl)-2,2-dichlorocyclopropane-1-carboxylicacid (C29) (0.150 g, 0.396 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.114 g,0.594 mmol) at room temperature. The reaction mixture was stirred atroom temperature for 72 hours, concentrated, and purified by silica gelflash column chromatography using 0-100% ethyl acetate/hexanes as eluentto give the title compound as a yellow foam (0.118 g, 45%). Thefollowing compounds were prepared in like manner to the procedureoutlined in Example 18:

trans-2-Chloro-5-(2,2-dichloro-3-(2-chloro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1004)

Isolated as a white foam (0.056 g, 61%).

trans-5-(3-(3-Bromo-4,5-dichlorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(4-fluorophenyl)benzamide(F1005)

Isolated as a yellow foam (0.1182 g, 45%).

trans-5-(3-(4-Bromo-3,5-dichlorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluorophenyl)benzamide(F1006)

Isolated as a yellow foam (0.0959 g, 77%).

trans-5-(3-(3-Bromo-4,5-dichlorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluorophenyl)benzamide(F1007)

Isolated as a yellow foam (0.0878 g, 70%).

trans-2-Chloro-5-(2,2-dichloro-3-(perfluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1009)

Isolated as a white foam (0.068 g, 71%).

trans-5-(3-(3-Bromo-4,5-difluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluorophenyl)benzamide(F1011)

Isolated as a white foam (0.060 g, 43%).

cis-5-(3-(3-Bromo-4,5-difluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluorophenyl)benzamide(F1012)

Isolated as a white foam (0.031 g, 22%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichloro-5-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1024)

Isolated as a white foam (0.071 g, 49%).

cis-2-Chloro-5-(2,2-dichloro-3-(3,4-dichloro-5-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1025)

Isolated as a white solid (0.023 g, 16%).

trans-5-(3-(3-Bromo-5-(pentafluoro-λ⁶-sulfanyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluorophenyl)benzamide(F1031)

Isolated as a white foam (0.066 g, 52%).

cis-5-(3-(3-Bromo-5-(pentafluoro-λ⁶-sulfanyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluorophenyl)benzamide(F1032)

Isolated as a clear colorless oil (0.031 g, 24%).

cis-2-Chloro-5-(2,2-dichloro-3-(3-chloro-2,4-difluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1033)

Isolated as a white foam (0.043 g, 29%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-2,4-difluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1034)

Isolated as a white foam (0.033 g, 22%).

trans-2-Cyano-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-N-methylbenzamide(F1039)

Isolated as a white foam (0.043 g, 38%).

trans-N-Allyl-2-chloro-N-(2-cyano-4-fluorophenyl)-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1055)

Isolated as an orange foam (0.144 g, 47%).

trans-2-Chloro-5-(3-(3,5-dichlorophenyl)-2,2-difluorocyclopropane-1-carboxamido)-N-(4-fluorophenyl)benzamide(F1057)

Isolated as an off-white solid (0.128 g, 84%).

trans-2-Chloro-5-(3-(3,5-dichlorophenyl)-2,2-difluorocyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1058)

Isolated as a white powder (0.127 g, 80%).

trans-tert-Butyl(3-(2-chloro-5-(3-(3,5-dichlorophenyl)-2,2-difluorocyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)carbamate(F1070)

Isolated as a white powder (0.150 g, 83%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(methylamino)phenyl)-N-methylbenzamide(F¹⁰⁷¹)

Isolated as a beige foam (0.061 g, 95%).

trans-2-Chloro-N-(2-cyano-4-fluorophenyl)-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(prop-2-yn-1-yl)benzamide(F1072)

Isolated as a yellow foam (0.066 g, 50%).

trans-(2-Chloro-N-(2-cyano-4-fluorophenyl)-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)methylacetate (F1084)

Isolated as a yellow film (0.026 g, 22%).

trans-2-Chloro-5-(2,2-dichloro-3-(4-iodophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1087)

Isolated as an off-white powder (0.14 g, 72%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-iodophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1088)

Isolated as a brown semisolid (0.14 g, 68%).

trans-2-Chloro-5-(2,2-dichloro-3-(4-(pentafluoro-λ⁶-sulfanyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1089)

Isolated as a white foam (0.14 g, 72%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-(pentafluoro-λ⁶-sulfanyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1090)

Isolated as a brown semisolid (0.15 g, 73%).

trans-2-Chloro-N-(2-cyano-4-fluorophenyl)-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-ethylbenzamide(F1091)

Isolated as a colorless film (0.083 g, 43%).

trans-N-Benzyl-2-chloro-N-(2-cyano-4-fluorophenyl)-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1099)

Isolated as a yellow foam (0.228 g, 60%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(4-iodophenyl)cyclopropane-1-carboxamido)benzamide(F1140)

Isolated as an off-white powder (0.087 g, 42%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3-iodophenyl)cyclopropane-1-carboxamido)benzamide(F1141)

Isolated as a gray foam (0.081 g, 40%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(4-(pentafluoro-λ⁶-sulfanyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1142)

Isolated as a white powder (0.073 g, 36%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3-(pentafluoro-λ⁶-sulfanyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1143)

Isolated as an off-white foam (0.074 g, 36%).

trans-2-chloro-5-(2,2-dichloro-3-(3-iodophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1281)

Isolated as a tan powder (0.078 g, 49%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-(pentafluoro-λ⁶-sulfanyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1293)

Isolated as a pale yellow foam (0.046 g, 29%).

tert-butylN-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropanecarbonyl]amino]benzoyl]-methyl-amino]-2,6-difluoro-phenyl]carbamate(CF1)

Isolated as a white foam (0.149 g, 65%): ¹H NMR (500 MHz, Methanol-d₄) δ7.92 (s, 0H), 7.84-7.59 (m, 2H), 7.59-7.42 (m, 4H), 7.28 (ddd, J=15.3,8.4, 2.1 Hz, 1H), 7.22 (d, J=8.9 Hz, 1H), 7.00 (t, J=9.2 Hz, 1H), 3.55(dd, J=16.9, 8.3 Hz, 1H), 3.41 (s, 3H), 3.25-3.19 (m, 1H), 3.13 (d,J=8.3 Hz, 1H), 1.41 (s, 8H), 1.34-1.22 (m, 9H); ¹⁹F NMR (471 MHz,Methanol-d₄) δ −119.20, −120.57, −121.26 (dt, J=9.4, 4.8 Hz), −124.91,−125.98; ESIMS m/z 792 ([M−H]⁻).

trans-tert-Butyl(3-(2-chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-methylbenzamido)-2,6-difluorophenyl)(methyl)carbamate(CF2)

Isolated as a white foam (0.081 g, 40.6%): ¹H NMR (500 MHz, Methanol-d₄)δ 7.90 (d, J=24.5 Hz, 1H), 7.71 (d, J=13.8 Hz, 1H), 7.56-7.44 (m, 3H),7.38 (s, 1H), 7.31-7.25 (m, 1H), 7.22 (dd, J=8.9, 1.8 Hz, 1H), 6.93 (t,J=9.1 Hz, 1H), 3.55 (dd, J=22.7, 8.3 Hz, 1H), 3.42 (d, J=1.7 Hz, 3H),3.22 (q, J=3.3 Hz, 1H), 3.18 (s, 0H), 3.14 (d, J=8.1 Hz, 1H), 3.09 (s,1H), 2.93 (s, 2H), 1.53-1.45 (m, 2H), 1.39-1.27 (m, 6H), 1.26-1.15 (m,3H); ¹⁹F NMR (471 MHz, Methanol-d₄) δ −118.58 (d, J=165.0 Hz), −119.80,−120.43, −124.14 (d, J=231.2 Hz), −126.04 (d, J=428.3 Hz); ESIMS m/z 730([M+Na]⁺).

tert-Butyl-N-((tert-butoxy)carbonyl)-N-(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)carbamate(DP7)

Isolated as a white solid (0.174 g, 67%).

trans-tert-Butyl(4-(2-chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-3-methylphenyl)carbamate(DP14)

Isolated as a white solid (2.75 g, 78%).

(1R,3R)-2,2-Dichloro-N-(4-chloro-3-(1,2-dimethyl-2-phenylhydrazine-1-carbonyl)phenyl)-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamide(F2544)

Isolated as a pale orange foam (0.266 g, 66%).

Example 19 Preparation oftrans-N-(3-amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-methylbenzamide(F1112)

Step 1: tert-ButylN-tert-butoxycarbonyl-N-[3-[(2-chloro-5-nitro-benzoyl)-methyl-amino]-2,6-difluoro-phenyl]carbamate(C144) (0.138 g, 0.225 mmol), ammonium chloride (0.0409 g, 0.764 mmol),and iron powder (0.0711 g, 1.273 mmol) were taken up in methanol (2.4mL) and water (0.8 mL) to give a black suspension. The reaction mixturewas heated to 60° C. for 5 hours. The reaction mixture was filtered andthe filtrate was washed with ethyl acetate. The combined organic layerswere washed with water, dried over magnesium sulfate, and evaporated togive the crude material as an orange oil, which was used withoutpurification.

Step 2: The crude aniline was dissolved in dichloromethane (2422 μL) togive an orange solution. 4.0 M Hydrogen chloride in 1,4-dioxane (606 μL,2.422 mmol) was added and the reaction mixture was stirred at roomtemperature overnight. The volatiles were removed. To the residue wasaddedtrans-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (C76) (0.077 g, 0.242 mmol) and N,N-dimethylpyridin-4-amine (0.0592g, 0.484 mmol) in dichloromethane (2422 μL) to give a yellow suspension.N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (69.6 mg,0.363 mmol) was added and everything went into solution, and thereaction mixture darkened to a deep blue color. The reaction mixture wasstirred at room temperature for 3 hours. The volatiles were removed.Purification by flash column chromatography using 0-100% ethylacetate/hexanes as eluent provided the title compound as a pale yellowfoam (0.061 g, 39%).

The following compounds were prepared in like manner to the procedureoutlined in Example 19:

trans-N-Allyl-N-(3-amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1113)

Isolated as a yellow foam (0.042 g, 49%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(prop-2-yn-1-yl)benzamide(F1114)

Isolated as a yellow foam (0.054 g, 35%).

Example 20 Preparation oftrans-2,6-dichloro-3-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1105)

To a solution oftrans-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxylicacid (C40) (0.040 g, 0.14 mmol),3-amino-2,6-dichloro-N-(2,4-difluorophenyl)benzamide (C129), (0.045 g,0.14 mmol), and pyridine (0.034 g, 0.43 mmol) in ethyl acetate (4 mL)was added a 50% solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.17mL, 0.28 mmol) in ethyl acetate. The resulting colorless solution wasstirred at 50° C. for 16 hours and cooled to room temperature. Thereaction mixture was adsorbed to Celite® (˜1.5 g) and purified byautomated flash chromatography using a gradient of 0-55% ethyl acetatein hexanes as eluent to give the title compound as a white solid (0.083g, 100%).

The following compounds were prepared in like manner to the procedureoutlined in Example 20:

tert-Butyl-(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)carbamate(F1053)

Isolated as a white foam (2.43 g, 89%).

trans-2-Chloro-5-(2,2-dichloro-3-(4-fluoro-3-methyl-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1066)

Isolated as a white foam (0.059 g, 31%).

cis-2-Chloro-5-(2,2-dichloro-3-(4-fluoro-3-methyl-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1067)

Isolated as a white foam (0.050 g, 26%).

trans-tert-Butyl-(3-(5-(3-(3-bromo-5-(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamido)-2,6-difluorophenyl)carbamate(F1073)

Isolated as a white solid (0.129 g, 82%).

tert-Butyl-(3-(2-chloro-5-((1S,3S)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)carbamate(F1074)

Isolated as a white solid (0.542 g, 73%).

trans-tert-Butyl-(3-(2-chloro-5-(2,2-dichloro-3-(4-chloro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)carbamate(F1077)

Isolated as a white solid (0.143 g, 85%).

trans-tert-Butyl-(3-(2-chloro-5-(2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)carbamate(F1078)

Isolated as a white solid (0.984 g, 85%).

trans-3-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-2,6-difluorobenzamide(F1086)

Isolated as a white solid (0.047 g, 68%).

trans-tert-Butyl-(3-(2-chloro-5-(2,2-dichloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)carbamate(F1092)

Isolated as a white solid (0.199 g, 86%).

trans-5-(3-(3-bromo-2,5-difluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluorophenyl)benzamide(F1093)

Isolated as a white foam (0.033 g, 30%).

cis-5-(3-(3-Bromo-2,5-difluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluorophenyl)benzamide(F1094)

Isolated as a clear colorless oil (0.042 g, 38%).

trans-tert-Butyl-(3-(5-(3-(3-bromo-2,5-difluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamido)-2,6-difluorophenyl)carbamate(F1095)

Isolated as a white solid (0.058 g, 26%).

trans-3-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,6-difluoro-N-(4-fluorophenyl)benzamide(F1100)

Isolated as a white solid (0.074 g, 91%).

trans-N-(4-Acetamidophenyl)-3-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,6-difluorobenzamide(F1101)

Isolated as a white solid (0.030 g, 90%).

trans-N-(4-Acetamidophenyl)-2,6-dichloro-3-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1102)

Isolated as a white solid (0.032 g, 71%).

trans-2,6-Dichloro-3-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(4-fluorophenyl)benzamide(F1103)

Isolated as a white solid (0.068 g, 88%).

trans-2,6-Dichloro-3-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-phenylbenzamide(F1104)

Isolated as a white solid (0.075 g, 94%).

trans-N-(4-Aminophenyl)-2,6-dichloro-3-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-methylbenzamide(F1106)

Isolated as a tan solid (0.038 g, 53%).

trans-tert-Butyl-N-tert-butoxycarbonyl-N-[3-[[2,6-dichloro-3-[[2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropanecarbonyl]amino]benzoyl]amino]-2,6-difluoro-phenyl]carbamate(F1107)

Isolated as a white solid (0.086 g, 80%).

trans-3-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,6-difluoro-N-phenylbenzamide(F1108)

Isolated as a tan solid (0.082 g, 96%).

trans-tert-Butyl-N-tert-butoxycarbonyl-N-[3-[[3-[[2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropanecarbonyl]amino]-2,6-difluorobenzoyl]amino]-2,6-difluorophenyl]carbamate(F1109)

Isolated as a tan solid (0.101 g, 73%).

trans-tert-Butyl-(3-(5-(3-(4-bromo-3-(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamido)-2,6-difluorophenyl)carbamate(F1115)

Isolated as a white foam (0.179 g, 85%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1118)

Isolated as a white foam (0.078 g, 83%).

trans-tert-Butyl-(3-(2-chloro-5-(2,2-dichloro-3-(3-chloro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)carbamate(F1119)

Isolated as a white solid (0.197 g, 88%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichloro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1147)

Isolated as a pale yellow foam (0.094 g, 52%).

cis-2-Chloro-5-(2,2-dichloro-3-(3,4-dichloro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1148)

Isolated as a clear, colorless oil (0.028 g, 15%).

trans-2-Chloro-5-(2,2-dichloro-3-(4-chloro-3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1163)

Isolated as a clear, colorless oil (0.115 g, 62%).

cis-2-Chloro-5-(2,2-dichloro-3-(4-chloro-3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1164)

Isolated as a white foam (0.040 g, 22%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1172)

Isolated as a white foam (0.076 g, 39%).

cis-2-Chloro-5-(2,2-dichloro-3-(3,5-dichloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1173)

Isolated as a white foam (0.032 g, 17%).

trans-2-chloro-5-(2,2-dichloro-3-(3-chloro-5-(pentafluoro-λ⁶-sulfanyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1232)

Isolated as a white foam (0.088 g, 50%).

cis-2-Chloro-5-(2,2-dichloro-3-(3-chloro-5-(pentafluoro-λ⁶-sulfanyl)phenyl)cyclopropane-1-carboxamido)-I-(2,4-difluorophenyl)benzamide(F1233)

Isolated as a clear, colorless oil (0.035 g, 20%).

tert-Butyl-N-tert-butoxycarbonyl-N-[34[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropanecarbonyl]amino]-3-fluorobenzoyl]amino]-2,6-difluorophenyl]carbamate(F1282)

Isolated as a white solid (0.284 g, 80%).

tert-Butyl-N-tert-butoxycarbonyl-N-[34[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropanecarbonyl]amino]-3-fluoro-benzoyl]amino]-2,6-difluorophenyl]carbamate(F1283)

Isolated as a white solid (0.298 g, 83%).

trans-2-Chloro-5-(2,2-dichloro-3-(2-chloro-5-(trifluoromethyl)phenyl)-cyclopropane-1-carboxamido)-N-(2,2,2-trifluoroethyl)benzamide(F2001)

Isolated as a white foam (0.047 g, 52%).

trans-2-Chloro-5-(2,2-dichloro-3-(perfluorophenyl)cyclopropane-1-carboxamido)-N-(2,2,2-trifluoroethyl)benzamide(F2002)

Isolated as a white solid (0.069 g, 76%).

trans-5-(3-(3-Bromo-4,5-difluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,2,2-trifluoroethyl)benzamide(F2003)

Isolated as a white foam (0.067 g, 51%).

cis-5-(3-(3-Bromo-4,5-difluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,2,2-trifluoroethyl)benzamide(F2004)

Isolated as a white foam (0.029 g, 22%).

trans-2,6-Dichloro-3-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,2,3,3,3-pentafluoropropyl)benzamide(F2005)

Isolated as a white solid (0.068 g, 93%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichloro-5-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,2,2-trifluoroethyl)benzamide(F2006)

Isolated as a clear colorless oil (0.077 g, 56%).

cis-2-Chloro-5-(2,2-dichloro-3-(3,4-dichloro-5-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,2,2-trifluoroethyl)benzamide(F2007)

Isolated as a clear colorless oil (0.022 g, 16%).

trans-5-(3-(3-Bromo-5-(pentafluoro-λ⁶-sulfanyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,2,2-trifluoroethyl)benzamide(F2008)

Isolated as a white foam (0.065 g, 54%).

cis-5-(3-(3-Bromo-5-(pentafluoro-λ⁶-sulfanyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,2,2-trifluoroethyl)benzamide(F2009)

Isolated as a clear colorless oil (0.028 g, 23%).

cis-2-Chloro-5-(2,2-dichloro-3-(3-chloro-2,4-difluorophenyl)cyclopropane-1-carboxamido)-N-(2,2,2-trifluoroethyl)benzamide(F2010)

Isolated as a white foam (0.039 g, 28%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-2,4-difluorophenyl)cyclopropane-1-carboxamido)-N-(2,2,2-trifluoroethyl)benzamide(F2011)

Isolated as a clear colorless oil (0.037 g, 26%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,2,2-trifluoroethyl)benzamide(F2012)

Isolated as a clear colorless oil (0.041 g, 31%).

cis-2-Chloro-5-(2,2-dichloro-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,2,2-trifluoroethyl)benzamide(F2013)

Isolated as a white foam (0.055 g, 42%).

trans-2-Chloro-5-(2,2-dichloro-3-(4-fluoro-3-methyl-5-(trifluoromethyl)phenyl)-cyclopropane-1-carboxamido)-N-(2,2,2-trifluoroethyl)benzamide(F2014)

Isolated as a white foam (0.068 g, 38%).

cis-2-Chloro-5-(2,2-dichloro-3-(4-fluoro-3-methyl-5-(trifluoromethyl)phenyl)-cyclopropane-1-carboxamido)-N-(2,2,2-trifluoroethyl)benzamide(F2015)

Isolated as a gold oil (0.045 g, 25%).

trans-3-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-ethyl-2,6-difluorobenzamide(F2016)

Isolated as a white solid (0.068 g, 91%).

trans-3-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,6-difluoro-N-(2,2,2-trifluoroethyl)benzamide(F2017)

Isolated as a white solid (0.081 g, 96%).

trans-3-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,6-difluoro-N-(2,2,3,3,3-pentafluoropropyl)benzamide(F2018)

Isolated as a white solid (0.068 g, 94%).

trans-2,6-Dichloro-3-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-ethylbenzamide(F2019)

Isolated as a white solid (0.077 g, 88%).

trans-2,6-Dichloro-3-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,2,2-trifluoroethyl)benzamide(F2020)

Isolated as a white solid (0.052 g, 66%).

trans-3-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,6-difluoro-N-propylbenzamide(F2021)

Isolated as a white foam (0.084 g, 91%).

trans-2,6-Dichloro-3-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-propylbenzamide(F2022)

Isolated as a white solid (0.077 g, 90%).

trans-3-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,6-difluoro-N-(3,3,3-trifluoropropyl)benzamide(F2023)

Isolated as a white solid 0.067 g, 82%).

trans-2,6-Dichloro-3-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(3,3,3-trifluoropropyl)benzamide(F2024)

Isolated as a white solid (0.071 g, 92%).

trans-2,6-Dichloro-3-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2-fluoroethyl)benzamide(F2025)

Isolated as a white solid (0.070 g, 84%).

trans-2,6-Dichloro-N-(3-chloropropyl)-3-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F2026)

Isolated as a white solid (0.070 g, 88%).

trans-3-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,6-difluoro-N-(2-fluoroethyl)benzamide(F2027)

Isolated as a white solid (0.088 g, 96%).

trans-N-(3-Chloropropyl)-3-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,6-difluorobenzamide(F2028)

Isolated as a white solid (0.083 g, 98%).

Example 21 Preparation oftrans-N-(3-amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(DP8)

Step 1: Preparation oftrans-tert-butyl-N-tert-butoxycarbonyl-N-[3-(5-(3-(4-fluoro3-trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamido)-2,6-difluorophenyl]carbamate.Anhydrous ethyl acetate (3 mL) was added to a 10 mL glass tubecontainingtrans-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (C76) (0.05 g, 0.158 mmol), andtert-butyl-N-((tert-butoxy)carbonyl)-N-(3-(5-amino-2-chlorobenzamido)-2,6-difluorophenyl)carbamate(C135) (0.079 g, 0.158 mmol) at room temperature. To the resultingsolution were then added pyridine (0.0374 g, 0.473 mmol) and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®,50% solution in ethyl acetate; 0.201 g, 0.315 mmol). The solution wasstirred at 24° C. for 12 hours, concentrated to dryness, and purified bysilica gel flash column chromatography using 0-50% ethyl acetate/hexanesas eluent to givetrans-tert-butyl-N-tert-butoxycarbonyl-N-[3-(5-(4-fluoro-3-(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamido)-2,6-difluorophenyl]carbamateas a white solid. (0.114 g, 86%).

Step 2: Preparation oftrans-N-(3-amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide.Anhydrous hydrogen chloride solution (4.0 M in dioxane; 0.326 mL, 1.305mmol) was added to a suspension oftrans-tert-butyl-N-tert-butoxycarbonyl-N-[3-(5-(3-(4-fluoro3-trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamido)-2,6-difluorophenyl]carbamate(0.104 g, 0.130 mmol). The suspension was stirred at 24° C. for 12hours. The dichloromethane was then removed under a stream of nitrogenand the sample was dissolved in ethyl acetate (20 mL) and washed withsaturated aqueous sodium bicarbonate (5 mL) and saturated aqueous sodiumchloride solution (5 mL). The ethyl acetate solution was dried overanhydrous magnesium sulfate, filtered and concentrated under vacuum on arotary evaporator. Purification of the residue with silica gel flashchromatography using 0-50% ethyl acetate/hexanes as eluent provided thetitle compound as a white foam (0.043 g, 53%).

The following compounds were prepared in like manner to the procedureoutlined in Example 21:

trans-N-(3-Amino-2,4-difluorophenyl)-5-(3-(3-bromo-5-(pentafluoro-λ⁶-sulfanyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamide(F1042)

Isolated as a white foam (0.079 g, 74%).

cis-N-(3-Amino-2,4-difluorophenyl)-5-(3-(3-bromo-5-(pentafluoro-λ⁶-sulfanyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamide(F1043)

Isolated as a clear, colorless oil (0.028 g, 56%).

trans-N-(3-Amino-2,4-difluorophenyl)-5-(3-(3-bromo-4,5-difluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamide(F1044)

Isolated as a clear, colorless oil (0.062 g, 56%).

cis-N-(3-Amino-2,4-difluorophenyl)-5-(3-(3-bromo-4,5-difluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamide(F1045)

Isolated as a clear, colorless oil (0.032 g, 53%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,4-dichloro-5-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1046)

Isolated as a white foam (0.085 g, 65%).

cis-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,4-dichloro-5-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1047)

Isolated as a clear colorless oil (0.026 g, 82%).

N-(3-amino-2,4-difluorophenyl)-2-chloro-5-((cis)-2,2-dichloro-3-(3-chloro-2,4-difluorophenyl)cyclopropane-1-carboxamido)benzamide(F1048)

Isolated as a white foam (0.053 g, 60%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3-chloro-2,4-difluorophenyl)cyclopropane-1-carboxamido)benzamide(F1049)

Isolated as a white solid (0.041 g, 63%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1050)

Isolated as a white foam (0.042 g, 30%).

cis-2-Chloro-5-(2,2-dichloro-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1051)

Isolated as a white foam (0.063 g, 46%).

N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(DP9)

Isolated as a white solid (1.5 g, 69%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(4-fluoro-3-methyl-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1068)

Isolated as a white foam (0.042 g, 44%).

cis-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-((cis)-2,2-dichloro-3-(4-fluoro-3-methyl-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1069)

Isolated as a white foam (0.032 g, 51%).

trans-N-(3-Amino-2,4-difluorophenyl)-5-(3-(3-bromo-5-(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamide(F1075)

Isolated as a clear, colorless oil (0.062 g, 66%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(4-chloro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1079)

Isolated as a white foam (0.068 g, 68%).

cis-(3-Amino-2,4-difluorophenyl)-5-(3-(3-bromo-2,5-difluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamide(F1097)

Isolated as a clear, colorless oil (0.019 g, 58%).

trans-N-(3-Amino-2,4-difluorophenyl)-5-(3-(3-bromo-2,5-difluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamide(F1098)

Isolated as a clear, colorless oil (0.014 g, 32%).

trans-N-(3-Amino-2,4-difluorophenyl)-5-(3-(4-bromo-3-(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamide(F1116)

Isolated as a white foam (0.140 g, 86%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3-chloro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1127)

Isolated as a clear, colorless oil (0.085 g, 61%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,4-dichloro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1149)

Isolated as a white foam (0.083 g, 81%).

cis-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,4-dichloro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1150)

Isolated as a clear, colorless oil (0.037 g, 70%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(4-chloro-3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1167)

Isolated as a white foam (0.072 g, 64%).

cis-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(4-chloro-3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1168)

Isolated as a clear, colorless oil (0.024 g, 63%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1181)

Isolated as a white foam (0.099 g, 68%).

cis-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1182)

Isolated as a white foam (0.038 g, 77%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3-chloro-5-(pentafluoro-λ⁶-sulfanyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1259)

Isolated as a clear, colorless oil (0.071 g, 70%).

cis-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3-chloro-5-(pentafluoro-λ⁶-sulfanyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1260)

Isolated as a clear, colorless oil (0.032 g, 67%).

Example 22 Preparation oftrans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-methoxyphenyl)benzamide(F1171)

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoicacid (C12) (0.1 g, 0.22 mmol) as a slurry in toluene (2 mL) was treatedwith oxalyl chloride (0.0.097 mL. 1.1 mmol) and a single drop ofN,N-dimethylformamide with stirring at room temperature. After themixture became homogeneous and gas evolution ceased, the solution wasconcentrated to a clear oil and then cooled in an ice bath undernitrogen. 2,4-Difluoro-3-methoxyaniline (0.035 g, 0.22 mmol) was addedas a solution in pyridine (2 mL) with stirring and the reaction mixturewas allowed to warm to room temperature and stir overnight. An aliquotwas removed and diluted with dimethyl sulfoxide and examined by liquidchromatography/mass spectroscopy which indicated a mixture of thedesired product and starting carboxylic acid. The reaction mixture waspartitioned between ethyl acetate and aqueous hydrochloric acid (1 N),the layers were separated, and the organic phase was dried over sodiumsulfate. Purification by flash silica gel chromatography (3:1hexane-ethyl acetate) gave the title compound as a green-tinted solid(0.075 g, 57%).

The following compounds were prepared in like manner to the procedureoutlined in Example 22:

trans-3-(2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenylacetate (F1193)

Isolated as a light yellow foam (0.105 g, 52%).

trans-Methyl3-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorobenzoate(F1265)

Isolated as a white foam (0.060 g, 44%).

Example 23 Preparation oftrans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-hydroxy-2-methylphenyl)benzamide(F1224)

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoicacid (C12) (0.221 g, 0.487 mmol), 4-amino-3-methylphenol (0.072 g, 0.59mmol) and 4-dimethylaminopyridine (0.071 g, 0.59 mmol) were weighed intoa round bottomed flask. N,N-Dimethylformamide (2 mL) was added viasyringe and -ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(0.19 g, 0.97 mmol) was added with stirring at room temperature. After64 hours, an aliquot was removed, diluted with dimethyl sulfoxide andanalyzed by liquid chromatography/mass spectroscopy which indicatedmultiple products. After 120 hours, the reaction mixture was partitionedbetween ethyl acetate and brine, the layers were separated and theorganic phase was dried over sodium sulfate. Purification by reversephase chromatography gave, in order of elution,trans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-hydroxy-2-methylphenyl)benzamide,isolated as an off-white solid (0.022 g, 8%) andtrans-4-amino-3-methylphenyl2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoate,isolated as an off-white solid (0.064 g, 24%): ¹H NMR (400 MHz,Acetone-d₆) δ 10.25 (br s, 1H), 8.40 (d, J=2.6 Hz, 1H), 7.96 (dd, J=8.8,2.7 Hz, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.50 (s, 3H), 6.92 (d, J=2.6 Hz,1H), 6.87 (dd, J=8.5, 2.7 Hz, 1H), 6.74 (d, J=8.5 Hz, 1H), 4.47 (ad,J=10.7 Hz, 2H), 3.67 (d, J=8.3 Hz, 1H), 3.46 (d, J=8.4 Hz, 1H), 2.17 (s,3H); ¹³C NMR (101 MHz, Acetone-d₆) δ 163.94, 162.59, 144.40, 141.76,137.93, 137.41, 134.71, 131.46, 130.64, 127.85, 127.38, 123.60, 122.74,122.46, 121.84, 119.33, 114.40, 61.91, 39.23, 37.55, 16.70; ESIMS m/z559 ([M+H]⁺).

Example 24 Preparation oftrans-tert-butyl-(4-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-3-methylphenyl)carbamate(DP10)

To a solution of tert-butyl (4-amino-3-methylphenyl)carbamate (C184)(0.052 g, 0.233 mmol) in dichloromethane (2 mL) was added3-(((ethylimino)methylene)amino)-N,N-dimethylpropan-1-aminehydrochloride (0.045 g, 0.233 mmol), N,N-dimethylpyridin-4-amine (0.021g, 0.171 mmol), andtrans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoicacid (C12) (0.075 g, 0.155 mmol). The reaction was stirred at roomtemperature for 14 hours. The reaction was directly loaded onto a Celiteloading column and purified by flash column chromatography using agradient of 0-30% ethyl acetate/hexanes as eluent to afford the titlecompound as a white solid (0.056 g, 55%): ¹H NMR (300 MHz, DMSO-d₆) δ10.91 (s, 1H), 9.90 (s, 1H), 9.32 (s, 1H), 7.90 (d, J=2.6 Hz, 1H), 7.74(dd, J=8.8, 2.6 Hz, 1H), 7.63 (t, J=1.8 Hz, 1H), 7.60-7.51 (m, 3H), 7.38(s, 1H), 7.25 (q, J=8.9 Hz, 2H), 3.64 (d, J=8.5 Hz, 1H), 3.52 (d, J=8.5Hz, 1H), 2.23 (s, 3H), 1.48 (s, 9H); (thin film) 3277, 2980, 1684, 1655,1539 cm⁻¹; ESIMS 656 ([M−H]⁻).

Example 25 Preparation oftert-butyl-N-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-carbonyl]amino]-3-fluorobenzoyl]amino]-2,6-difluorophenyl]carbamate(F1239)

To a solution of2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzoicacid (C1) (0.360 g, 0.79 mmol) in ethyl acetate (2.5 mL) were addedtert-butylN-(3-amino-2,6-difluoro-phenyl)-N-tert-butoxycarbonylcarbamate (C182)(0.327 g, 0.95 mmol), and pyridine (0.188 g, 0.191 mL, 2.37 mmol)followed by a 50% solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.94mL, 1.58 mmol) in ethyl acetate, and the resulting gold solution waswarmed to 45° C. and stirred for 68 hours. The reaction mixture wasconcentrated and the viscous, amber residue was dissolve in minimalmethylene chloride (˜3 mL) and adsorbed to Celite®. The adsorbedmaterial was purified by automated flash chromatography using a gradientof 0-25% ethyl acetate in hexanes as eluent to give the title compound(0.166 g, 87%) as a white solid.

The following compounds were prepared in like manner to the procedureoutlined in Example 25:

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(3-fluoro-2-nitrophenyl)benzamide(F1081)

Isolated as a yellow solid (0.056 g, 43%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2-fluoro-4-methyl-5-nitrophenyl)benzamide(F1082)

Isolated as an off-white foam (0.109 g, 81%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(4,5-difluoro-2-nitrophenyl)benzamide(F1085)

Isolated as a yellow film (0.039 g, 28%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1268)

Isolated as a white powder (0.049 g, 34%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1269)

Isolated as a white solid (0.078 g, 55%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1270)

Isolated as a white foam (0.084 g, 58%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoro-N-methylacetamido)-2,4-difluorophenyl)benzamide(F1271)

Isolated as a white foam (0.090 g, 61%).

trans-N-(3-Bromo-4-fluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1304)

Isolated as an off-white solid (0.18 g, 33%).

trans-N-(2-Bromo-4-fluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1305)

Isolated as an off-white solid (0.18 g, 37%).

trans-N-(4-Bromo-2-fluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1306)

Isolated as an off-white solid (0.18 g, 37%).

trans-N-(3-Bromo-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1307)

Isolated as an off-white solid (0.33 g, 39%).

trans-N-(5-Bromo-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1308)

Isolated as an off-white solid (0.48 g, 34%).

trans-N-(2-Bromo-4,6-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1309)

Isolated as an off-white solid (0.24 g, 28%).

trans-N-(3-Bromo-4,5-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(DP11)

Isolated as an off-white solid (0.62 g, 44%).

trans-N-(3-Amino-2,4,5,6-tetrafluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1022)

Isolated as a white foam (0.012 g, 8%).

trans-tert-Butyl-(3-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,4-difluorophenyl)carbamate(F1023)

Isolated as a white foam (0.088 g, 56%).

trans-N-(3-Acetamido-2,4-dimethylphenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1128)

Isolated as a white solid (0.094 g, 66%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,3-dimethyl-4-nitrophenyl)benzamide(F1180)

Isolated as a yellow solid (0.246 g, 70%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,5-dimethyl-4-nitrophenyl)benzamide(F1230)

Isolated as a white solid (0.041 g, 12%).

trans-N-(4-Bromo-2-methylphenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1054)

Isolated as a white powder (0.46 g, 84%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluoro-N-(4-fluorophenyl)benzamide(F1152)

Isolated as a pale-yellow solid (0.065 g, 88%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-3-fluorobenzamide(F1153)

Isolated as a pale-yellow solid (0.071 g, 93%).

trans-N-(4-Acetamidophenyl)-2-chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1154)

Isolated as a white solid (0.077 g, 97%).

trans-tert-Butyl-N-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropanecarbonyl]amino]-3-fluorobenzoyl]amino]-2,6-difluorophenyl]carbamate(F1155)

Isolated as a light-yellow-solid (0.0185 g, 85%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-methyl-N-phenylbenzamide(F1183)

Isolated as a white solid (0.072 g, 89%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(4-fluorophenyl)-3-methylbenzamide(F1184)

Isolated as a tan solid (0.071 g, 86%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-3-methylbenzamide(F1185)

Isolated as a white solid (0.070 g, 84%).

trans-N-(4-Acetamidophenyl)-2-chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1186)

Isolated as a light pink solid (0.067 g, 74%).

trans-tert-Butyl-N-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropanecarbonyl]amino]-3-methylbenzoyl]amino]-2,6-difluorophenyl]carbamate(F1187)

Isolated as a light tan solid (0.109 g, 88%).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-methyl-N-phenylbenzamide(F1188)

Isolated as a white solid (0.073 g, 93%).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(4-fluorophenyl)-2-methylbenzamide(F1189)

Isolated as a light tan solid (0.072 g, 89%).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-2-methylbenzamide(F1190)

Isolated as a light-tan solid (0.073 g, 90%).

trans-N-(4-Acetamidophenyl)-3-chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-methylbenzamide(F1191)

Isolated as a white solid (0.081 g, 93%).

trans-tert-Butyl-N-tert-butoxycarbonyl-N-[3-[[3-chloro-5-[[2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropanecarbonyl]amino]-2-methylbenzoyl]amino]-2,6-difluorophenyl]carbamate(F1192)

Isolated as a white solid (0.131 g, 99%).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluoro-N-phenylbenzamide(F1194)

Isolated as an off-white solid (0.043 g, 44%).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluoro-N-(4-fluorophenyl)benzamide(F1195)

Isolated as an off-white solid (0.072 g, 71%).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-2-fluorobenzamide(F1196)

Isolated as an off-white solid (0.064 g, 61%).

trans-N-(4-Acetamidophenyl)-3-chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluorobenzamide(F1197)

Isolated as a white solid (0.044 g, 40%).

trans-tert-Butyl-N-tert-butoxycarbonyl-N-[3-[[3-chloro-5-[[2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropanecarbonyl]amino]-2-fluorobenzoyl]amino]-2,6-difluorophenyl]carbamate(F1198)

Isolated as an off-white solid (0.099 g, 65%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,3-difluoro-N-phenylbenzamide(F1207)

Isolated as an off-white solid (0.066 g, 67%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,3-difluoro-N-(4-fluorophenyl)benzamide(F1208)

Isolated as a white solid (0.079 g, 77%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-2,3-difluorobenzamide(F1209)

Isolated as a white solid (0.089 g, 84%).

trans-N-(4-Acetamidophenyl)-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzamide(F1210)

Isolated as a white solid (0.086 g, 78%).

trans-tert-Butyl-N-tert-butoxycarbonyl-N-[3-[[5-[[2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropanecarbonyl]amino]-2,3-difluorobenzoyl]amino]-2,6-difluorophenyl]carbamate(F1211)

Isolated as a light yellow solid (0.130 g, 89%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-phenyl-3-(trifluoromethyl)benzamide(F1212)

Isolated as a tan solid (0.060 g, 76%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluoro-2-methoxy-N-phenylbenzamide(F1213)

Isolated as a tan solid (0.067 g, 86%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(4-fluorophenyl)-3-(trifluoromethyl)benzamide(F1214)

Isolated as a tan solid (0.066 g, 83%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-3-(trifluoromethyl)benzamide(F1215)

Isolated as a tan foam (0.072 g, 88%).

trans-N-(4-Acetamidophenyl)-2-chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-(trifluoromethyl)benzamide(F1216)

Isolated as a tan solid (0.072 g, 83%).

trans-tert-Butyl-N-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[2,2-dichloro-3-(3-chloro-4-fluoro-phenyl)cyclopropanecarbonyl]amino]-3-(trifluoromethyl)-benzoyl]amino]-2,6-difluorophenyl]carbamate(F1217)

Isolated as a light-yellow solid (0.098 g, 86%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluoro-N-(4-fluorophenyl)-2-methoxybenzamide(F1218)

Isolated as a tan foam (0.072 g, 89%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-3-fluoro-2-methoxybenzamide(F1219)

Isolated as a white solid (0.065 g, 79%).

trans-N-(4-Acetamidophenyl)-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)-cyclopropane-1-carboxamido)-3-fluoro-2-methoxybenzamide(F1220)

Isolated as a light-yellow solid (0.075 g, 87%).

trans-tert-Butyl-N-tert-butoxycarbonyl-N-[3-[[5-[[2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropanecarbonyl]amino]-3-fluoro-2-methoxybenzoyl]amino]-2,6-difluorophenyl]carbamate(F1221)

Isolated as a light-yellow solid (0.109 g, 94%).

trans-tert-Butyl-N-tert-butoxycarbonyl-N-[4-[[2-chloro-5-[[2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropanecarbonyl]amino]benzoyl]amino]-2,6-difluoro-phenyl]carbamate(F1266)

Isolated as a light brown solid (2.06 g, 79%).

tert-Butyl-N-((tert-butoxy)carbonyl)-N-(5-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,4-difluorophenyl)carbamate(DP12)

Isolated as a white solid (0.154 g, 90%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-fluoro-2-nitrophenyl)benzamide(DP13)

Isolated as a yellow solid (0.8 g, 42%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluoro-N-(4-fluorophenyl)-2-methylbenzamide(F1278)

Isolated as a light-tan solid (0.058 g, 85%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-3-fluoro-2-methylbenzamide(F1279)

Isolated as a light-tan solid (0.059 g, 84%).

trans-tert-Butyl-N-tert-butoxycarbonyl-N-[3-[[5-[[2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropanecarbonyl]amino]-3-fluoro-2-methylbenzoyl]amino]-2,6-difluorophenyl]carbamate(F1280)

Isolated as a white solid (0.099 g, 100%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-ethyl-2-fluoro-3-methylbenzamide(F2029)

Isolated as a white solid (0.068 g, 83%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluoro-3-methyl-N-(2,2,2-trifluoroethyl)benzamide(F2030)

Isolated as a white solid (0.077 g, 84%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluoro-3-methyl-N-(2,2,3,3,3-pentafluoropropyl)benzamide(F2031)

Isolated as a white solid (0.083 g, 82%).

trans-N-(3-Chloropropyl)-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)-cyclopropane-1-carboxamido)-2-fluoro-3-methylbenzamide(F2032)

Isolated as a white solid (0.069 g, 78%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-ethyl-3-fluorobenzamide(F2033)

Isolated as a white solid (0.046 g, 71%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluoro-N-(2,2,2-trifluoroethyl)benzamide(F2034)

Isolated as a white solid (0.061 g, 85%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluoro-N-(2,2,3,3,3-pentafluoropropyl)benzamide(F2035)

Isolated as a white solid (0.070 g, 89%).

trans-2-Chloro-N-(3-chloropropyl)-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F2036)

Isolated as a white solid (0.063 g, 87%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-ethyl-3-methylbenzamide(F2037)

Isolated as a white solid (0.055 g, 77%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-methyl-N-(2,2,2-trifluoroethyl)benzamide(F2038)

Isolated as a tan solid (0.052 g, 66%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-methyl-N-(2,2,3,3,3-pentafluoropropyl)benzamide(F2039)

Isolated as a white solid (0.080 g, 93%).

trans-2-Chloro-N-(3-chloropropyl)-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F2040)

Isolated as a white solid (0.054 g, 69%).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-ethyl-2-methylbenzamide(F2041)

Isolated as a white solid (0.031 g, 44%).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-methyl-N-(2,2,2-trifluoroethyl)benzamide(F2042)

Isolated as a white solid (0.066 g, 83%).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-methyl-N-(2,2,3,3,3-pentafluoropropyl)benzamide(F2043)

Isolated as a white solid (0.071 g, 82%).

trans-3-Chloro-N-(3-chloropropyl)-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-methylbenzamide(F2044)

Isolated as a tan solid (0.050 g, 64%).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluoro-N-(2,2,2-trifluoroethyl)benzamide(F2045)

Isolated as a white solid (0.047 g, 47%).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluoro-N-(2,2,3,3,3-pentafluoropropyl)benzamide(F2046)

Isolated as an off-white solid (0.074 g, 68%).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-ethyl-2-fluorobenzamide(F2047)

Isolated as an off-white solid (0.062 g, 70%).

trans-3-Chloro-N-(3-chloropropyl)-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluorobenzamide(F2048)

Isolated as an off-white solid (0.062 g, 63%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,3-difluoro-N-(2,2,2-trifluoroethyl)benzamide(F2049)

Isolated as a white solid (0.079 g, 79%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,3-difluoro-N-(2,2,3,3,3-pentafluoropropyl)benzamide(F2050)

Isolated as a white solid (0.092 g, 84%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-ethyl-2,3-difluorobenzamide(F2051)

Isolated as a white solid (0.073 g, 82%).

trans-N-(3-Chloropropyl)-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzamide(F2052)

Isolated as a white solid (0.075 g, 76%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-ethyl-3-(trifluoromethyl)benzamide(F2053)

Isolated as a pale-yellow solid (0.045 g, 64%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,2,2-trifluoroethyl)-3-(trifluoromethyl)benzamide(F2054)

Isolated as a white foam (0.062 g, 80%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-(trifluoromethyl)-N-(3,3,3-trifluoropropyl)benzamide(F2055)

Isolated as a white solid (0.063 g, 79%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,2,3,3,3-pentafluoropropyl)-3-(trifluoromethyl)benzamide(F2056)

Isolated as a white foam (0.053 g, 62%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-ethyl-3-fluoro-2-methoxybenzamide(F2057)

Isolated as a white foam (0.054 g, 76%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluoro-2-methoxy-N-(2,2,2-trifluoroethyl)benzamide(F2058)

Isolated as a white foam (0.069 g, 86%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluoro-2-methoxy-N-(3,3,3-trifluoropropyl)benzamide(F2059)

Isolated as a white foam (0.070 g, 86%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluoro-2-methoxy-N-(2,2,3,3,3-pentafluoropropyl)benzamide(F2060)

Isolated as a white foam (0.069 g, 81%).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-methoxy-N-(2,2,2-trifluoroethyl)benzamide(F2061)

Isolated as a white solid (0.060 g, 77%).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-methoxy-N-(2,2,3,3,3-pentafluoropropyl)benzamide(F2062)

Isolated as a white solid (0.075 g, 88%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluoro-2-methyl-N-(2,2,2-trifluoroethyl)benzamide(F2063)

Isolated as a white solid (0.063 g, 96%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluoro-2-methyl-N-(2,2,3,3,3-pentafluoropropyl)benzamide(F2064)

Isolated as a white solid (0.059 g, 81%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluoro-N-(4-fluorophenyl)-3-methylbenzamide(F1136)

Isolated as a tan solid (0.078 g, 81%).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-2-fluoro-3-methylbenzamide(F1137)

Isolated as a tan foam (0.082 g, 87%).

trans-tert-Butyl-N-tert-butoxycarbonyl-N-[3-[[5-[[2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropanecarbonyl]amino]-2-fluoro-3-methylbenzoyl]amino]-2,6-difluorophenyl]carbamate(F1138)

Isolated as a white solid (0.149 g, 83%).

trans-N-(4-Acetamidophenyl)-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)-cyclopropane-1-carboxamido)-2-fluoro-3-methylbenzamide(F1139)

Isolated as a white solid (0.088 g, 85%).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(4-fluorophenyl)-2-methoxybenzamide(F1235)

Isolated as a white solid (0.048 g, 60%).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-2-methoxybenzamide(F1236)

Isolated as a white solid (0.059 g, 72%).

trans-tert-Butyl-N-tert-butoxycarbonyl-N-[3-[[3-chloro-5-[[2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropanecarbonlyl]amino]-2-methoxybenzoyl]amino]-2,6-difluorophenyl]carbamate(F1237)

Isolated as an off-white solid (0.059 g, 52%).

Example 26 Preparation oftrans-2-((tert-butoxycarbonyl)(4-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-3-methylphenyl)amino)ethylacetate (F1129)

Step 1: Preparation of2-((tert-butoxycarbonyl)(3-methyl-4-nitrophenyl)amino)ethyl acetate.tert-Butyl (3-methyl-4-nitrophenyl)carbamate (C223) (1.0 g, 3.96 mmol)dissolved in anhydrous N,N-dimethylformamide (5 mL) was added dropwiseto a stirred suspension of sodium hydride (60% oil dispersion, 0.206 g,5.15 mmol) in anhydrous N,N-dimethylformamide (50 mL) at a rate thatmaintained the temperature below 30° C. Upon completion of the addition,the resulting orange solution was stirred at room temperature for 30minutes followed by the dropwise addition of 2-bromoethyl acetate (0.662g, 3.96 mmol). The resulting solution was stirred at room temperaturefor 12 hours, then carefully quenched with water (100 mL), and extractedwith ethyl acetate (3×50 mL). The organic extracts were washedsuccessively with water and saturated aqueous sodium chloride solution,dried over anhydrous magnesium sulfate, and concentrated under vacuum ona rotary evaporator. Purification by silica gel flash chromatographyprovided the title compound as a yellow oil (0658 g, 47%): ¹H NMR (400MHz, CDCl₃) δ 8.04-7.97 (m, 1H), 7.26 (m, 2H), 4.31-4.23 (m, 2H), 3.93(t, J=5.6 Hz, 2H), 2.62 (s, 3H), 1.97 (s, 3H), 1.48 (s, 9H); ¹³C NMR(101 MHz, CDCl₃) δ 170.72, 170.58, 153.57, 146.91, 145.94, 134.81,129.85, 125.53, 124.40, 81.83, 77.37, 77.05, 76.73, 62.16, 62.08, 48.76,28.21, 20.86, 20.76, 20.70; ESIMS m/z 339 ([M+H]+).

Step 2: Preparation of2-((4-amino-3-methylphenyl)(tert-butoxycarbonyl)amino)ethyl acetate.Palladium hydroxide (10% w/w; 0.135 g, 0.096 mmol) was added to astirred solution of2-((tert-butoxycarbonyl)(3-methyl-4-nitrophenyl)amino)ethyl acetate(0.650 g, 1.92 mmol) dissolved in ethyl acetate (50 mL). The flask wasevacuated and filled with hydrogen via a balloon adapter, and theresulting black suspension was stirred for 13 hours at room temperature.The reaction mixture was filtered through a pad of Celite® andconcentrated under vacuum on a rotary evaporator to give the titlecompound as a brown solid (0.527 g, 85%): ¹H NMR (400 MHz, CDCl₃) δ 6.85(s, 2H), 6.61 (d, J=8.2 Hz, 1H), 4.18 (t, J=5.8 Hz, 2H), 3.79 (t, J=5.8Hz, 2H), 3.60 (s, 2H), 2.14 (s, 3H), 2.00 (s, 3H), 1.40 (s, 9H); ESIMSm/z 309 ([M+H]⁺).

Step 3: Preparation oftrans-2-((tert-butoxycarbonyl)(4-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-3-methylphenyl)amino)ethylacetate (F1129). 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (T3P®, 50% solution in ethyl acetate; 0.281 g, 0.441mmol) was added dropwise to a stirred solution oftrans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoicacid (C12) (0.100 g, 220 mmol),2-((4-amino-3-methylphenyl)(tert-butoxycarbonyl)amino)ethyl acetate(0.068 g, 0.220 mmol), and pyridine (0.053 g, 0.661 mmol) in anhydrousethyl acetate (3 mL). The solution was stirred for 12 hours at 23° C.and concentrated. Purification by silica gel flash chromatography gavethe title compound as a white foam (0.149 g, 86%).

The following compounds were prepared in like manner to the procedureoutlined in Example 26:

trans-tert-Butyl-(4-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-3-methylphenyl)(2-cyanoethyl)carbamate(F1157)

Isolated as a white solid (0.134 g, 81%).

trans-tert-Butyl-(4-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-3-methylphenyl)(2-methoxyethyl)carbamate(F1159)

Isolated as a clear colorless oil (0.121 g, 73%).

Example 27 Preparation ofN-(4-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1027)

To a solution of2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoicacid (C13) (0.100 g, 0.220 mmol) andtert-butyl-N-((tert-butoxy)carbonyl)-N-(4-amino-3,5-difluorophenyl)carbamate(C181) (0.076 g, 0.220 mmol) in ethyl acetate (2 mL) were added pyridine(0.036 mL, 0.441 mmol) and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®)as a 50% solution in ethyl acetate (0.210 g, 0.331 mmol). The mixturewas warmed to 45° C. for 48 hours. The reaction mixture was cooled toroom temperature and concentrated under a stream of nitrogen. Theresidue was purified by flash column chromatography using 0-30% ethylacetate/hexanes as eluent. Product fractions were combined andconcentrated under reduced pressure. The resulting residue was dissolvedin dichloromethane (2 mL), and a 4 M solution of hydrogen chloride indioxane (0.545 mL, 2.18 mmol) was added. The reaction mixture wasstirred at room temperature for 18 hours. The solvent was evaporatedunder a stream of nitrogen. The residue was partitioned between ethylacetate and saturated aqueous sodium bicarbonate. The phases wereseparated, the organic layer was washed with saturated aqueous sodiumbicarbonate and brine and then passed through a phase separator to dry,and the solvent was concentrated. Purification by flash columnchromatography using 0-30% ethyl acetate/hexanes as eluent afforded thetitle compound as a white solid (0.025 g, 19%).

The following compounds were prepared in like manner to the procedureoutlined in Example 27:

N-(4-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1028)

Isolated as a white solid (0.019 g, 15%).

N-(4-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1029)

Isolated as a white solid (0.022 g, 17%).

N-(4-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1030)

Isolated as a white solid (0.019 g, 14%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3-(difluoromethyl)-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1036)

Isolated as a white solid (0.080 g, 42%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(4-chloro-3-(difluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1037)

Isolated as a white solid (0.086 g, 46%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3-chloro-5-(difluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1038)

Isolated as a light yellow foam (0.079 g, 42%).

trans-N-(3-Amino-2,6-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1026)

Isolated as a white foam (0.037 g, 76%).

trans-N-(4-Amino-2-methylphenyl)-2-chloro-5-(2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(DP1)

Isolated as a white foam (0.838 g, 99%).

Example 28 Preparation oftrans-2,2-dichloro-N-(4-chloro-3-(2-(pyridin-2-yl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2502)

To a solution oftrans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoicacid (C12) (0.080 g, 0.176 mmol) and 2-(1-methylhydrazinyl)pyridine(0.033 g, 0.265 mmol) in ethyl acetate (2 mL) at room temperature wereadded sequentially diisopropylethylamine (0.123 mL, 0.706 mmol) and2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (T3P®;0.225 g, 0.353 mmol) as a 50% solution in ethyl acetate. The reactionmixture was stirred for 18 hours at room temperature and thenconcentrated under a stream of nitrogen. Purification by columnchromatography using 0-100% ethyl acetate/hexanes as eluent afforded thetitle compound as a yellow solid (0.019 g, 20%).

The following compounds were prepared in like manner to the procedureoutlined in Example 28:

trans-2,2-dichloro-N-(4-chloro-3-(2-(4-chloro-3-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2501)

Isolated as a light yellow foam (0.058 g, 44%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-methyl-2-(pyridin-2-yl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2503)

Isolated as a yellow solid (0.046 g, 47%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(5-chloropyridin-2-yl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2504)

Isolated as an off-white solid (0.045 g, 44%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(3-chloropyridin-2-yl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2505)

Isolated as an off-white solid (0.036 g, 35%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(6-chloropyridazin-3-yl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2506)

Isolated as a light yellow solid (0.070 g, 69%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-methyl-2-(4-(trifluoromethyl)pyridin-2-yl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2507)

Isolated as a white solid (0.096 g, 86%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(pyri midin-2-yl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2508)

Isolated as a white solid (0.027 g, 28%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(pyrimidin-4-yl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2509)

Isolated as a white solid (0.016 g, 17%).

(1R,3R)-2,2-Dichloro-N-(4-chloro-3-(2-methyl-2-phenylhydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2510)

Isolated as a white solid (0.045 g, 37%).

(1R,3R)-2,2-Dichloro-N-(4-chloro-3-(2-methyl-2-phenylhydrazine-1-carbonyl)phenyl)-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamide(F2511)

Isolated as a white solid (0.048 g, 40%).

(1R,3R)-2,2-Dichloro-N-(4-chloro-3-(2-methyl-2-phenylhydrazine-1-carbonyl)phenyl)-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboximide(F2512)

Isolated as a white solid (0.041 g, 33%).

(1R,3R)-2,2-Dichloro-N-(4-chloro-3-(2-methyl-2-phenylhydrazine-1-carbonyl)phenyl)-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamide(F2513)

Isolated as a white solid (0.057 g, 46%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(4-fluorophenyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2553)

Isolated as a yellow foam (0.036 g, 31%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(4-cyanophenyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2554)

Isolated as a light foam (0.070 g, 63%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(4-nitrophenyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2555)

Isolated as an orange solid (0.146 g, 66%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-phenylhydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2556)

Isolated as an off-white foam (0.0911 g, 82%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-methyl-2-phenylhydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2557)

Isolated as an off-white foam (0.094 g, 85%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(2,5-difluorophenyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2558)

Isolated as an off-white foam (0.0796 g, 72%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(2,4-difluorophenyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2559)

Isolated as an off-white foam (0.089 g, 80%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(3,4-dichlorophenyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2560)

Isolated as a light brown foam (0.072 g, 60%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(2,5-dichlorophenyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2561)

Isolated as a light brown foam (0.095 g, 79%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(4-fluoro-2-methylphenyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2562)

Isolated as a light brown foam (0.080 g, 71%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(4-methoxyphenyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2563)

Isolated as a light brown foam (0.039 g, 35%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(4-(trifluoromethoxy)phenyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2564)

Isolated as a light brown foam (0.082 g, 63%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(4-(perfluoroethoxy)phenyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2565)

Isolated as a light brown foam (0.105 g, 79%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(4-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2571)

Isolated as an off-white foam (0.048 g, 38%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(3-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2572)

Isolated as a light brown foam (0.054 g, 43%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(2-(trifluoromethyl)phenyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2573)

Isolated as a light brown foam (0.107 g, 86%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-methyl-2-(m-tolyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2574)

Isolated as an off-white foam (0.103 g, 88%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(p-tolyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2575)

Isolated as a light brown foam (0.030 g, 26%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(2-cyanophenyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2576)

Isolated as a light yellow foam (0.058 g, 50%).

Example 29 Preparation oftrans-N-(3-(2-acetylhydrazine-1-carbonyl)-4-chlorophenyl)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2514)

To a solution oftrans-2,2-dichloro-N-(4-chloro-3-(hydrazinecarbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamidehydrochloride (F2567) (0.25 g, 0.498 mmol) in tetrahydrofuran (5 mL) wasadded triethylamine (0.15 g, 1.49 mmol) and acetic anhydride (0.061 g,0.598 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 16 hours. The reaction mixture was concentrated underreduced pressure, and the residue was dissolved in ethyl acetate (20 mL)and washed with water (2×10 mL) and brine (5 mL). The organic layer wasdried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. Purification by column chromatography eluting with40-60% ethyl acetate/petroleum ether afforded the title compound as awhite solid (0.08 g, 32%).

The following compounds were prepared in like manner to the procedureoutlined in Example 29:

trans-2,2-Dichloro-N-(4-chloro-3-(2-(2,2,2-trifluoroacetyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2515)

Isolated as a white solid (0.06 g, 21%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(3,3,3-trifluoropropanoyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2516)

Isolated as a white solid (0.06 g, 26%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(2,2-difluorocyclopropane-1-carbonyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2517)

Isolated as a white solid (0.07 g, 31%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(1-cyanocyclopropane-1-carbonyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2518)

Isolated as a white solid (0.07 g, 31%).

trans-N-(3-(2-Benzoylhydrazine-1-carbonyl)-4-chlorophenyl)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2519)

Isolated as a white solid (0.15 g, 68%).

trans-N-(3-(2-Acetyl-2-methylhydrazine-1-carbonyl)-4-chlorophenyl)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2522)

Isolated as an off-white solid (0.02 g, 10%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-methyl-2-(2,2,2-trifluoroacetyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2523)

Isolated as an off-white solid (0.085 g, 38%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(2-cyclopropylacetyl)-2-methylhydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2524)

Isolated as an off-white solid (0.04 g, 18%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(1-cyanocyclopropane-1-carbonyl)-2-methylhydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2525)

Isolated as an off-white solid (0.11 g, 50%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(dimethylglycyl)-2-methylhydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2526)

Isolated as an off-white solid (0.11 g, 50%).

trans-N-(3-(2-Benzoyl-2-methylhydrazine-1-carbonyl)-4-chlorophenyl)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2527)

Isolated as an off-white solid (0.12 g, 48%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(2-cyclopropylacetyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2528)

Isolated as a white solid (0.11 g, 50%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(2-methoxyacetyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2529)

Isolated as an off-white solid (0.09 g, 42%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(dimethylglycyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2530)

Isolated as an off-white foam (0.06 g, 25%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-picolinoylhydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2531)

Isolated as an off-white solid (0.055 g, 26%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(3,3,3-trifluoro-2-(trifluoromethyl)propanoyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2532)

Isolated as an off-white solid (0.04 g, 16%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-methyl-2-(3,3,3-trifluoropropanoyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2533)

Isolated as an off-white solid (0.085 g, 38%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(2,2-difluorocyclopropane-1-carbonyl)-2-methylhydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2534)

Isolated as an off-white solid (0.065 g, 29%).

Example 30 Preparation oftrans-2-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoyl)-N-(2,2,2-trifluoroethyl)hydrazine-1-carboxamide(F2535)

To a solution oftrans-2,2-dichloro-N-(4-chloro-3-(hydrazinecarbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamidehydrochloride (F2567) (0.175 g, 0.347 mmol) in tetrahydrofuran (4 mL)were added triethylamine (0.105 g, 1.04 mmol) and1,1,1-trifluoro-2-isocyanatoethane (0.052 g, 0.417 mmol) at 0° C. Thereaction mixture was stirred at room temperature for 16 hours. Thereaction mixture was concentrated under reduced pressure, and theresidue was dissolved in ethyl acetate (20 mL) and washed with water(2×10 mL) and brine (5 mL). The organic layer was dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure.Purification by column chromatography eluting with 40-60% ethylacetate/petroleum ether afforded the title compound as an off-whitesolid (0.10 g, 48%).

The following compounds were prepared in like manner to the procedureoutlined in Example 30:

trans-2-(2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoyl)-N-isopropylhydrazine-1-carboxamide(F2536)

Isolated as an off-white solid (0.13 g, 61%).

trans-2-(2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoyl)-N-phenylhydrazine-1-carboxamide(F2537)

Isolated as an off-white solid (0.06 g, 26%).

trans-2-(2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoyl)-N-(cyclopropylmethyl)hydrazine-1-carboxamide(F2538)

Isolated as an off-white solid (0.11 g, 50%).

Example 31 Preparation oftrans-2,2-dichloro-N-(4-chloro-3-(2-((2,2,2-trifluoroethyl)carbamothioyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2539)

To a solution oftrans-2,2-dichloro-N-(4-chloro-3-(hydrazinecarbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamidehydrochloride (F2567) (0.190 g, 0.377 mmol) in tetrahydrofuran (4 mL)were added triethylamine (0.114 g, 1.13 mmol) and1,1,1-trifluoro-2-isothiocyanatoethane (0.064 g, 0.452 mmol) at 0° C.The reaction mixture was stirred at room temperature for 16 hours. Thereaction mixture was concentrated under reduced pressure, and theresidue was dissolved in ethyl acetate (20 mL) and washed with water(2×10 mL) and brine (5 mL). The organic layer was dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure.Purification by column chromatography eluting with 40-60% ethylacetate/petroleum ether afforded the title compound as an off-whitesolid (0.08 g, 35%).

The following compounds were prepared in like manner to the procedureoutlined in Example 31:

trans-2,2-Dichloro-N-(4-chloro-3-(2-(isopropylcarbamothioyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2540)

Isolated as an off-white solid (0.06 g, 27%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(phenylcarbamothioyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2541)

Isolated as an off-white solid (0.07 g, 26%).

Example 32 Preparation of trans-ethyl2-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoyl)hydrazine-1-carboxylate(F2542)

To a solution oftrans-2,2-dichloro-N-(4-chloro-3-(hydrazinecarbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamidehydrochloride (F2567) (0.175 g, 0.347 mmol) in tetrahydrofuran (4 mL)were added triethylamine (0.114 g, 1.13 mmol) and ethyl chloroformate(0.049 g, 0.452 mmol) at 0° C. The reaction mixture was stirred at roomtemperature for 16 hours. The reaction mixture was concentrated underreduced pressure, and the residue was dissolved in ethyl acetate (20 mL)and washed with water (2×10 mL) and brine (5 mL). The organic layer wasdried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. Purification by column chromatography eluting with40-60% ethyl acetate/petroleum ether afforded the title compound as anoff-white solid (0.04 g, 19%).

The following compounds were prepared in like manner to the procedureoutlined in Example 32:

trans-Trifluoromethyl2-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoyl)hydrazine-1-carboxylate(F2543)

Isolated as an off-white solid (0.05 g, 21%).

Example 33 Preparation oftrans-2,2-dichloro-N-(4-chloro-3-(2-(4-fluorobenzyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2570)

To a 50 mL flask were addedtrans-2,2-dichloro-N-(4-chloro-3-(hydrazinecarbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2567) (0.10 g, 0.214 mmol), methanol (3 mL) and 4-fluorobenzaldehyde(0.023 mL, 0.214 mmol). The reaction mixture was stirred at roomtemperature overnight. The solution was concentrated and the residuepurified by column chromatography using 0-100% ethyl acetate/hexanes asgradient to afford the imine product as a colorless foam. The foam wasdissolved in methanol (3 mL) and to the solution were added sequentiallysodium borohydride (0.081 g, 1.283 mmol) and acetic acid (0.024 mL,0.428 mmol). The reaction mixture was stirred overnight at roomtemperature. Saturated aqueous sodium bicarbonate solution (5 mL) wasadded carefully to the reaction mixture, and the mixture was extractedwith ethyl acetate (10 mL). The organic layer was dried over sodiumsulfate, filtered, and concentrated to afford the title compound as acolorless foam (0.065 g, 48%).

The following compounds were prepared in like manner to the procedureoutlined in Example 33:

trans-2,2-dichloro-N-(4-chloro-3-(2-(4,4-difluorocyclohexyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2569)

Isolated as an off-white foam (0.030 g, 22%).

Example 34 Preparation oftrans-2,2-dichloro-N-(4-chloro-3-(2-(2,4-difluorobenzyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2547)

To a solution oftrans-2,2-dichloro-N-(4-chloro-3-(2-(2,4-difluorobenzylidene)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F3004) (0.20 g, 0.34 mmol) in ethanol (6 mL) were added acetic acid(0.1 mL) and sodium cyanoborohydride (0.107 g, 1.7 mmol) at 0° C. andthe reaction mixture was stirred at room temperature for 16 hours. Thereaction mixture was poured into water (10 mL) and extracted with ethylacetate (2×10 mL). The organic layer was dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. Purificationby column chromatography using 20-40% ethyl acetate/petroleum ether aseluent afforded the title compound as an off-white solid (0.155 g, 77%).

The following compounds were prepared in like manner to the procedureoutlined in Example 34:

trans-2,2-Dichloro-N-(4-chloro-3-(2-(1-phenylethyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2548)

Isolated as an off-white solid (0.175 g, 70%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(cyclopropylmethyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2549)

Isolated as an off-white solid (0.085 g, 40%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(3,3,3-trifluoropropyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2550)

Isolated as an off-white solid (0.080 g, 35%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(1-methoxypropan-2-yl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2551)

Isolated as an off-white solid (0.085 g, 33%).

trans-2,2-Dichloro-N-(4-chloro-3-(1-methyl-2-(3,3,3-trifluoropropyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2552)

Isolated as an off-white solid (0.10 g, 55%).

trans-N-(3-(2-Benzylhydrazine-1-carbonyl)-4-chlorophenyl)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2545)

Isolated as an off-white solid (0.100 g, 28%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(2,5-difluorobenzyl)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F2546)

Isolated as an off-white solid (0.04 g, 32%).

Example 35 Preparation oftrans-N-(3-(2-Benzylidenehydrazine-1-carbonyl)-4-chlorophenyl)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F3001)

To a solution oftrans-2,2-dichloro-N-(4-chloro-3-(hydrazinecarbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamidehydrochloride (F2567) (0.300 g, 0.60 mmol) in ethanol (8.0 mL) was addedsodium acetate trihydrate (0.099 g, 1.2 mmol) at room temperature andthe mixture was stirred for 15 min. Benzaldehyde (0.19 g, 1.8 mmol) wasadded followed by acetic acid (0.1 mL), and the reaction mixture wasstirred at room temperature for 16 hours. The reaction mixture waspoured into water (10 mL) and extracted with ethyl acetate (2×10 mL).The organic layer was dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure. Purification by columnchromatography using 20-40% ethyl acetate/petroleum ether as eluentafforded the title compound as a pale brown solid (0.110 g, 35%).

The following compounds were prepared in like manner to the procedureoutlined in Example 35:

trans-2,2-Dichloro-N-(4-chloro-3-(2-(pyridin-2-ylmethylene)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F3002)

Isolated as an off-white solid (0.125 g, 33%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(2,5-difluorobenzylidene)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F3003)

Isolated as an off-white solid (0.13 g, 34%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(2,4-difluorobenzylidene)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F3004)

Isolated as an off-white solid (0.105 g, 32%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(1-phenylethylidene)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F3005)

Isolated as an off-white solid (0.100 g, 38%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(thiazol-2-ylmethylene)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F3006)

Isolated as a pale yellow solid (0.080 g, 30%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(cyclopropylmethylene)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F3007)

Isolated as a pale yellow solid (0.100 g, 30%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(3,3,3-trifluoropropylidene)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F3008)

Isolated as an off-white solid (0.300 g, 40%).

trans-2,2-Dichloro-N-(4-chloro-3-(2-(propan-2-ylidene)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F3010)

Isolated as an off-white foam (0.05 g, 41%).

Example 36 Preparation oftrans-2,2-dichloro-N-(4-chloro-3-(1-methyl-2-(3,3,3-trifluoropropylidene)hydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamide(F3009)

To a solution oftrans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoicacid (C12) (0.50 g, 1.10 mmol) in dichloromethane (10 mL) were addedsequentially N,N-dimethylformamide (3 drops) and oxalyl chloride (0.14mL, 1.66 mmol) at 0° C., and the reaction mixture was stirred at roomtemperature for 3 hours. The reaction mixture was then concentratedunder reduced pressure (bath temperature was maintained at 30-35° C.).The acid chloride was dissolved in dichloromethane (6 mL) and was addedto a solution of 1-methyl-2-(3,3,3-trifluoropropylidene)hydrazine (C220)(0.600 g (crude)) and triethylamine (0.46 mL, 3.3 mmol) indichloromethane (10 mL) at 0° C. The reaction mixture was stirred atroom temperature for 10 hours. The reaction mixture was diluted withdichloromethane (20 mL) and washed with water. The organic layer wasdried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. Purification by column chromatography using 20-40%ethyl acetate/petroleum ether as eluent afforded the title compound as apink solid (0.320 g, 50%).

Example 37 Preparation oftrans-2,2-dichloro-N-(4-chloro-3-(hydrazinecarbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamidehydrochloride (F2567)

To a solution of trans-tert-butyl2-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoyl)hydrazine-1-carboxylate(F2566) (1.00 g, 1.77 mmol) in dichloromethane (10 mL) was added 4 M HClin 1,4-dioxane (5 mL) at 0° C. and the reaction mixture was stirred at20° C. for 16 hours. The reaction mixture was concentrated under reducedpressure. The residue was triturated with diethyl ether. and theresulting solid was filtered and dried under vacuum. The title compoundwas isolated as an off-white solid (0.600 g, 68%).

The following compounds were prepared in like manner to the procedureoutlined in Example 37:

trans-2,2-Dichloro-N-(4-chloro-3-(2-methylhydrazine-1-carbonyl)phenyl)-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamidehydrochloride (F2521)

Isolated as a white solid (2.6 g, 78%).

Example 38 Preparation of trans-tert-butyl2-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoyl)hydrazine-1-carboxylate(F2566)

To a solution oftrans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoicacid (C12) (7.60 g, 16.9 mmol) in dichloromethane (200 mL) was addedtert-butyl hydrazine carboxylate (2.20 g, 16.9 mmol) and3-(((ethylimino)methylene) amino)-N,N-dimethylpropan-1-aminehydrochloride (EDC; 3.20 g, 16.9 mmol). The reaction mixture was stirredat room temperature for 16 hours. The reaction mixture was concentratedunder reduced pressure and the residue was taken up in water andextracted with ethyl acetate (2×200 mL). The organic layer was washedwith saturated aqueous sodium bicarbonate solution (50 mL), dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure. Purification by column chromatography eluting with 10% ethylacetate in petroleum ether afforded the title compound as an off-whitesolid (1.20 g, 22%).

The following compounds were prepared in like manner to the procedureoutlined in Example 38:

trans-tert-Butyl2-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoyl)-1-methylhydrazine-1-carboxylate(F2520)

Isolated as an off-white solid (2.6 g, 78%).

Example 39 Preparation of2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzoicacid (C1)

Step 1: To a suspension of(1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxylicacid (C93) (0.445 g, 1.57 mmol) in 1,2-dichloroethane (10 mL) were addedtwo drops of N,N-dimethylformamide followed by the dropwise addition ofoxalyl dichloride (1.992 g, 15.7 mmol), and the resulting light-yellowmixture was stirred at room temperature for 16 hours. The solvent andexcess oxalyl dichloride were evaporated under reduced pressure, and theresulting gold oil was dissolved in 1,2-dichloroethane (10 mL) andconcentrated (repeated 2×) to give the intermediate acid chloride as agold oil which was used without purification.

Step 2: To a mixture of 5-amino-2-chloro-3-fluorobenzoic acid (C196)(0.357 g, 1.88 mmol) and triethylamine (0.334 g, 3.30 mmol) in1,2-dichloroethane (15 mL) was added a solution of the freshly preparedacid chloride,(1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carbonylchloride (0.474 g, 1.57 mmol), dropwise at 0° C., and the resultinggreen solution was stirred under nitrogen while warming to roomtemperature over a 1-hour period, and then stirred at room temperaturefor 3 hours. The reaction mixture was concentrated to a dark oil, andthe oil was partitioned between ethyl acetate (100 mL) and 1 normalaqueous hydrogen chloride (25 mL). The phases were separated and theaqueous layer was extracted with additional ethyl acetate (25 mL). Thecombined organic extracts were washed with brine (50 mL), dried oversodium sulfate, filtered, and concentrated to an amber oil. The oil wasdissolved in minimal ethyl acetate and adsorbed to Celite®. The adsorbedmaterial was purified by reverse-phase, automated flash chromatographyusing a gradient of 10-100% acetonitrile in water as eluent to give thetitle compound as a light tan solid (0.398 g, 55%): mp 205-208° C.; ¹HNMR (400 MHz, DMSO-d₆) δ 13.78 (s, 1H), 11.12 (s, 1H), 7.92 (d, J=10.8Hz, 2H), 7.71 (dd, J=7.1, 1.8 Hz, 1H), 7.54-7.39 (m, 2H), 3.59 (d, J=8.4Hz, 1H), 3.43 (d, J=8.4 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −111.57,−117.24; HRMS-ESI (m/z) [M+]⁺ calcd for C₁₇H₉Cl₄F₂NO₃, 452.9305; found,452.9303.

The following compounds were prepared in like manner to the procedureoutlined in Example 39:

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzoicacid (C2)

Isolated as a light tan solid (0.740 g, 50%): mp 186-189° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 13.78 (s, 1H), 11.12 (s, 1H), 7.92 (d, J=10.6 Hz,2H), 7.71 (d, J=7.1 Hz, 1H), 7.57-7.38 (m, 2H), 3.59 (d, J=8.4 Hz, 1H),3.43 (d, J=8.5 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −111.54, −117.23;ESIMS m/z 454 ([M−H]⁻).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluoro-3-methylbenzoicacid (C3)

Isolated as a tan solid (1.229 g, 87%): mp 228-235° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 13.25 (s, 1H), 10.76 (s, 1H), 7.99 (dd, J=6.1, 2.8 Hz, 1H),7.75 (dd, J=6.2, 2.8 Hz, 1H), 7.70 (dd, J=7.1, 2.0 Hz, 1H), 7.53-7.40(m, 2H), 3.56 (d, J=8.4 Hz, 1H), 3.39 (d, J=8.5 Hz, 1H), 2.27 (d, J=2.1Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −117.31, −120.17; ESIMS m/z 434([M−H]⁻).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-methylbenzoicacid (C4)

Isolated as a light-tan solid (0.875 g, 69%): mp 218-222° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 13.42 (s, 1H), 10.84 (s, 1H), 7.90 (d, J=2.6 Hz,1H), 7.80-7.63 (m, 2H), 7.59-7.33 (m, 2H), 3.56 (d, J=8.4 Hz, 1H), 3.41(d, J=8.4 Hz, 1H), 2.38 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −117.29;ESIMS m/z 450 ([M−H]⁻).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-methylbenzoicacid (C5)

Isolated as a tan solid (0.780 g, 63%): mp 219-225° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 13.34 (s, 1H), 10.90 (s, 1H), 8.02 (d, J=2.3 Hz, 1H), 7.96(d, J=2.3 Hz, 1H), 7.71 (dd, J=7.1, 1.9 Hz, 1H), 7.52-7.40 (m, 2H), 3.57(d, J=8.4 Hz, 1H), 3.40 (d, J=8.5 Hz, 1H), 2.49 (s, 3H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −117.29; ESIMS m/z 450 ([M−H]⁻).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-(trifluoromethyl)benzoicacid (C6)

Isolated as an off-white solid (0.800 g, 47%): mp 216-219° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 14.00 (s, 1H), 11.23 (s, 1H), 8.33-8.23 (m, 2H),7.72 (dd, J=7.1, 1.9 Hz, 1H), 7.56-7.39 (m, 2H), 3.60 (d, J=8.4 Hz, 1H),3.44 (d, J=8.5 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −61.39, −117.21;ESIMS m/z 503 ([M−2H]⁻).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluoro-2-methoxybenzoicacid (C7)

Isolated as a tan solid (0.760 g, 50%): mp 183-186° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 13.28 (s, 1H), 10.91 (s, 1H), 7.93-7.78 (m, 1H), 7.78-7.66(m, 2H), 7.47 (d, J=9.0 Hz, 2H), 3.83 (s, 3H), 3.57 (d, J=8.4 Hz, 1H),3.40 (d, J=8.5 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −117.29, −128.27;ESIMS m/z 450 ([M−H]⁻).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluorobenzoicacid (C8)

Isolated as a tan solid (0.82 g, 48%): mp 217-224° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 13.70 (s, 1H), 11.01 (s, 1H), 8.13 (dd, J=6.1, 2.8 Hz, 1H),8.06 (dd, J=5.8, 2.7 Hz, 1H), 7.71 (dd, J=7.2, 1.9 Hz, 1H), 7.54-7.38(m, 2H), 3.59 (d, J=8.4 Hz, 1H), 3.41 (d, J=8.5 Hz, 1H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −117.25, −119.42; ESIMS m/z 453 ([M−H]⁻).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzoicacid (C9)

Isolated as a white solid (0.93 g, 57%): mp 222-226° C.; ¹H NMR (400MHz, DMSO-d₆) δ 11.03 (s, 1H), 8.05-7.87 (m, 2H), 7.71 (dd, J=7.1, 1.9Hz, 1H), 7.46 (dd, J=8.0, 4.1 Hz, 2H), 3.58 (d, J=8.4 Hz, 1H), 3.41 (d,J=8.5 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −117.26, −135.55 (d, J=22.4Hz), −142.67 (d, J=22.4 Hz); ESIMS m/z 437 ([M−H]⁻).

trans-3-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-methoxybenzoicacid (C10)

Isolated as a light tan solid (0.380 g, 22%): ¹H NMR (400 MHz, DMSO-d₆)δ 13.38 (s, 1H), 10.91 (s, 1H), 8.03 (d, J=2.7 Hz, 1H), 7.90 (d, J=2.7Hz, 1H), 7.70 (dd, J=7.1, 2.0 Hz, 1H), 7.54-7.38 (m, 2H), 3.81 (s, 3H),3.57 (d, J=8.4 Hz, 1H), 3.40 (d, J=8.5 Hz, 1H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −117.28; ESIMS m/z 466 ([M−H]⁻).

trans-5-(2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluoro-2-methylbenzoicacid (C11)

Isolated as a white solid (0.304 g, 53%): mp 210-212° C.; ¹H NMR (400MHz, DMSO-d₆) δ 13.26 (s, 1H), 10.94 (s, 1H), 7.88 (d, J=2.2 Hz, 1H),7.77 (dd, J=11.8, 2.1 Hz, 1H), 7.70 (dd, J=7.1, 1.9 Hz, 1H), 7.46 (dd,J=7.8, 4.3 Hz, 2H), 3.57 (d, J=8.4 Hz, 1H), 3.41 (d, J=8.4 Hz, 1H), 2.38(d, J=2.0 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −114.04, −117.29;HRMS-ESI (m/z) [M⁺]⁺ calcd for C₁₈H₁₂Cl₃F₂NO₃, 432.9851; found,432.9856.

trans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoicacid (C12)

Isolated as a light brown solid (0.421 g, 93%): mp 234-236° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 13.47 (s, 1H), 10.90 (s, 1H), 8.16 (d, J=2.3 Hz,1H), 7.78 (dd, J=8.7, 2.4 Hz, 1H), 7.59 (m, 4H), 3.56 (dd, J=49.8, 8.5Hz, 2H), 1.09 (m, 1H); ¹³C NMR (101 MHz, DMSO-d₆) δ 166.26, 165.77,162.61, 137.57, 137.27, 134.04, 132.18, 131.44, 131.22, 127.88, 127.66,126.40, 125.92, 122.88, 121.17, 102.37, 62.11, 38.41, 36.83; ESIMS m/z454 ([M+H]⁺).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzoicacid (C13)

Isolated as a grey solid (3.80 g, 96%): ¹H NMR (300 MHz, DMSO-d₆) δ13.48 (s, 1H), 10.90 (s, 1H), 8.15 (d, J=2.6 Hz, 1H), 7.78 (dd, J=8.8,2.7 Hz, 1H), 7.63 (t, J=1.9 Hz, 1H), 7.57-7.50 (m, 3H), 3.62 (d, J=8.5Hz, 1H), 3.49 (d, J=8.5 Hz, 1H); ESIMS m/z 454 ([M+H]⁺).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzoicacid (C14)

Isolated as a grey solid (3.70 g, 98%): ¹H NMR (300 MHz, DMSO-d₆) δ13.47 (s, 1H), 10.95 (s, 1H), 8.16 (d, J=2.7 Hz, 1H), 7.82-7.73 (m, 2H),7.69 (d, J=8.3 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H), 7.43 (dd, J=8.5, 2.1 Hz,1H), 3.60 (d, J=8.5 Hz, 1H), 3.45 (d, J=8.5 Hz, 1H); ESIMS m/z 454([M+H]⁺).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)benzoicacid (C15)

Isolated as a grey solid (3.60 g, 99%): ¹H NMR (400 MHz, DMSO-d₆) δ13.44 (s, 1H), 10.91 (s, 1H), 8.16 (d, J=2.7 Hz, 1H), 7.80-7.76 (m, 3H),7.54 (d, J=8.7 Hz, 1H), 3.63 (dt, J=8.5, 0.7 Hz, 1H), 3.52 (d, J=8.5 Hz,1H); ESIMS m/z 488 ([M+H]⁺).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzoicacid (C16)

Isolated as a grey solid (3.80 g. 99%): ¹H NMR (400 MHz, DMSO-d₆) δ13.48 (s, 1H), 10.93 (s, 1H), 8.16 (d, J=2.6 Hz, 1H), 7.78 (dd, J=8.8,2.7 Hz, 1H), 7.71 (dd, J=7.2, 2.0 Hz, 1H), 7.53 (d, J=8.7 Hz, 1H),7.50-7.42 (m, 2H), 3.58 (d, J=8.4 Hz, 1H), 3.42 (d, J=8.5 Hz, 1H); ¹⁹FNMR (376 MHz, DMSO-d₆) δ −117.29; ESIMS m/z 438 ([M+H]⁺).

Example 40 Preparation ofcis/trans-3-(3-bromo-4,5-difluorophenyl)-2,2-dichlorocyclopropane-1-carboxylicacid (C17)

Step 1: Preparation of(E/Z)-1-bromo-2,3-difluoro-5-(4-methoxystyryl)benzene. N-Butyllithium(2.5 Molar (M) in hexane) (3.62 mL, 9.05 mmol) was added to a stirredsuspension of (4-methoxybenzyl)triphenylphosphonium chloride (3.79 g,9.05 mmol) in dry tetrahydrofuran (50 mL) at −30° C. The resultingheterogeneous dark red mixture was stirred at −25-−30° C. for 30minutes, followed by the dropwise addition of a solution of3-bromo-4,5-difluorobenzaldehyde (2 g, 9.05 mmol) in anhydroustetrahydrofuran (5 mL). The resulting suspension of white solid wasstirred at −30° C. for another 2 hours, then allowed to warm to ambienttemperature and stirred for another 12 hours. The reaction mixture wasquenched with water (100 mL) and extracted with diethyl ether (3×50 mL).The organic extracts were washed successively with water and saturatedaqueous sodium chloride solution, dried over anhydrous magnesiumsulfate, and concentrated under vacuum on a rotary evaporator.Purification by silica gel flash chromatography provided the titlecompound as a clear colorless oil (1.6 g, 54%, approx. 1:1 mixture of E-and Z-stilbenes): EIMS m/z 325.

Step 2: Preparation of1-bromo-5-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)-2,3-difluorobenzene.To a stirred solution of(E/Z)-1-bromo-2,3-difluoro-5-(4-methoxystyryl)benzene (1.165 g, 3.58mmol) and tetrabutylammonium hexafluorophosphate(V) (0.139 g, 0.358mmol) in chloroform (28.7 mL) were added sodium hydroxide powder (1.433g, 35.8 mmol) and water (200 μL) at 23° C. The resulting mixture wasvigorously stirred at 50-55° C. for 16 hours. The reaction mixture wasdiluted with water and extracted with dichloromethane. The combinedorganic layers were dried over sodium sulfate, filtered, andconcentrated. Purification by silica gel flash column chromatographyprovided the title compound as a pale yellow oil (1.7 g, 63%, approx.2:1 cis- to trans-cyclopropanes): EIMS m/z 325

Step 3. Preparation ofcis/trans-3-(3-bromo-4,5-difluorophenyl)-2,2-dichlorocyclopropane-1-carboxylicacid. Ruthenium(III) chloride hydrate (0.047 g, 0.207 mmol) was added toa stirred mixture of crudecis/trans-3-(3-bromo-4,5-difluorophenyl)-2,2-dichlorocyclopropane-1-carboxylicacid (1.69 g, 4.14 mmol) in water:ethyl acetate:acetonitrile (2.5:1:1,90 mL) at 23° C. Sodium periodate (13.29 g, 62.1 mmol) was carefullyadded portionwise at a rate to maintain the temperature below 50° C. Theresulting biphasic brown mixture was vigorously stirred at 23° C. for 2hours. The reaction mixture was diluted with water (200 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers weredried over magnesium sulfate, filtered, and concentrated. The residuewas dissolved in minimal acetonitrile and purified by C-18 flashchromatography to give the title compound as a grey solid (0.665 g, 44%approx. 2:1 mixture of trans/cis cyclopropanes): ¹H NMR (400 MHz,CDCl₃CDCl₃) δ 8.90 (s, 1H), 7.42-7.21 (m, 1H), 7.10 (dddd, J=26.8, 9.3,6.6, 2.1 Hz, 1H), 3.35 (dd, J=49.0, 9.6 Hz, 1H), 3.01-2.77 (m, 1H); ¹⁹FNMR (376 MHz, CDCl₃) δ −129.47, −129.53, −130.16, −130.21, −132.59,−132.64, −133.35, −133.41; ESIMS m/z 345 ([M−H]⁻).

The following compounds were prepared in like manner to the procedureoutlined in Example 40:

cis/trans-2,2-Dichloro-3-(3,4-dichloro-5-fluorophenyl)cyclopropane-1-carboxylicacid (C18)

Isolated as a grey solid (0.459 g, 44%, approx. 3:1 trans/cis): ¹H NMR(400 MHz, CDCl₃CDCl₃) δ 8.73 (s, 1H), 7.20 (d, J=1.7 Hz, 1H), 7.14-6.91(m, 1H), 3.36 (dd, J=51.9, 9.6 Hz, 1H), 2.91 (dd, J=47.1, 9.6 Hz, 1H);¹⁹F NMR (376 MHz, CDCl₃) δ −108.55, −109.27; ESIMS m/z 317 ([M−H]⁻).trioxatriphosphinanecis/trans-3-(3-Bromo-5-(pentafluoro-λ⁶-sulfanyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylicacid (C19)

Isolated as a grey solid (0.260 g, 40%, approx. 2:1 trans/cis): ¹H NMR(400 MHz, CDCl₃CDCl₃) δ 10.43 (s, 1H), 7.88 (dt, J=13.2, 1.9 Hz, 1H),7.75-7.48 (m, 2H), 3.613.29 (m, 1H), 2.96 (dd, J=38.3, 9.6 Hz, 1H);ESIMS m/z 435 ([M−H]⁻).

cis/trans-2,2-Dichloro-3-(3-chloro-2,4-difluorophenyl)cyclopropane-1-carboxylicacid (C20)

Isolated as a grey solid (0.656 g, 35%, approx. 1:1 trans/cis): ¹H NMR(400 MHz, CDCl₃CDCl₃) δ 9.27 (s, 1H), 7.35 (q, J=7.5 Hz, 1H), 7.11-6.90(m, 1H), 3.33 (dd, J=104.1, 9.5 Hz, 1H), 3.06-2.77 (m, 1H); ¹⁹F NMR (376MHz, CDCl₃) δ −111.34, −111.35, −111.40, −111.41, −112.05, −112.06,−113.13, −113.14; ESIMS m/z 300 ([M−H]⁻).

cis/trans-2,2-Dichloro-3-(3-chloro-2-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (C21)

Isolated as a grey solid (0.485 g, 31%, approx. 2:1 trans/cis): ¹H NMR(400 MHz, CDCl₃CDCl₃) δ 9.02 (s, 1H), 7.87-7.61 (m, 1H), 7.39-7.23 (m,1H), 3.60-3.19 (m, 1H), 3.14-2.85 (m, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ−62.32, −108.88, −110.51; ESIMS m/z 350 ([M−H]⁻).

cis/trans-2,2-Dichloro-3-(4-fluoro-3-methyl-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (C22)

Isolated as a green oil (1.42 g, 66%, approx. 3:1 trans/cis): ¹H NMR(400 MHz, CDCl₃CDCl₃) δ 7.33 (dd, J=21.3, 6.3 Hz, 2H), 6.82 (s, 1H),3.38 (dd, J=50.6, 9.7 Hz, 1H), 3.04-2.82 (m, 1H), 2.34 (dd, J=10.0, 2.3Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −61.53, −118.49, −119.16; ESIMS m/z330 ([M−H]⁻).

cis/trans-3-(3-Bromo-2,5-difluorophenyl)-2,2-dichlorocyclopropane-1-carboxylicacid (C23)

Isolated as a grey solid (0.545 g, 51%, approx. 1:1 trans/cis): ¹H NMR(400 MHz, CDCl₃CDCl₃) δ 9.97 (s, 1H), 7.29 (dtt, J=7.1, 4.4, 2.3 Hz,1H), 7.00 (dddd, J=137.6, 8.2, 5.3, 3.5 Hz, 1H), 3.52-3.10 (m, 1H),3.07-2.74 (m, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −112.49, −112.53, −114.36,−114.40, −115.73, −115.77, −116.17, −116.21; ESIMS m/z 345 ([M−H]⁻).

cis/trans-2,2-Dichloro-3-(3,4-dichloro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (C24)

Isolated as a tan solid (0.295 g, 25%, approx. 2:1 trans/cis): ¹H NMR(400 MHz, CDCl₃CDCl₃) δ 7.71-7.45 (m, 2H), 6.48 (s, 1H), 3.38 (dd,J=62.2, 9.6 Hz, 1H), 2.95 (dd, J=41.0, 9.6 Hz, 1H); ¹⁹F NMR (376 MHz,CDCl₃) δ −63.01; ESIMS m/z 366 ([M−H]⁻).

cis/trans-2,2-Dichloro-3-(4-chloro-3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (C25)

Isolated as a grey solid (0.392 g, 33%, approx. 3:1 trans/cis): ¹H NMR(400 MHz, CDCl₃CDCl₃) δ 9.56 (s, 1H), 7.55-7.36 (m, 1H), 7.28 (dd,J=8.8, 2.0 Hz, 1H), 3.41 (dd, J=59.6, 9.6 Hz, 1H), 2.95 (dd, J=46.2, 9.6Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −62.50, −109.97, −110.78; ESIMS m/z350 ([M−H]⁻).

cis/trans-2,2-Dichloro-3-(3,5-dichloro-4-fluorophenyl)cyclopropane-1-carboxylicacid (C26)

Isolated as a grey solid (0.889 g, 48%, approx. 2:1 trans/cis): ¹H NMR(400 MHz, CDCl₃CDCl₃) δ 9.83 (s, 1H), 7.54-6.93 (m, 2H), 3.34 (dd,J=50.9, 9.6 Hz, 1H), 2.89 (dd, J=46.6, 9.6 Hz, 1H); ¹⁹F NMR (376 MHz,CDCl₃) δ −115.34, −115.98; ESIMS m/z 317 ([M−H]⁻).

cis/trans-2,2-Dichloro-3-(3-chloro-5-(pentafluoro-λ⁶-sulfanyl)phenyl)cyclopropane-1-carboxylicacid (C27)

Isolated as a grey solid (0.412 g, 35%, approx. 3:1 trans/cis): ¹H NMR(400 MHz, CDCl₃CDCl₃) δ 7.81-7.69 (m, 1H), 7.63-7.38 (m, 2H), 5.95 (s,1H), 3.61-3.31 (m, 1H), 3.11-2.87 (m, 1H); ESIMS m/z 390 ([M−H]⁻).

cis/trans-2,2-Dichloro-3-(perfluorophenyl)cyclopropane-1-carboxylic acid(C28)

Isolated as a white solid (1.44 g, 67%): ¹H NMR (400 MHz, CDCl₃) δ 10.19(s, 1H), 3.30 (d, J=8.2 Hz, 1H), 3.09 (d, J=8.3 Hz, 1H); ¹⁹F NMR (376MHz, CDCl₃) δ −140.52, −140.54, −140.58, −140.60, −152.14, −152.20,−152.25, −160.82, −160.84, −160.87, −160.89, −160.93, −160.95; ESIMS m/z320 ([M−H]⁻).

trans-3-(3-Bromo-4,5-dichlorophenyl)-2,2-dichlorocyclopropane-1-carboxylicacid (C29)

Isolated as a white foam (1.3 g, 54%): ¹H NMR (400 MHz, CDCl₃) δ 7.537.42 (m, 1H), 7.35 (d, J=2.0 Hz, 1H), 3.41 (d, J=8.3 Hz, 1H), 2.86 (d,J=8.2 Hz, 1H). ESIMS m/z 376 ([M−H]⁻).

trans-3-(4-Bromo-3,5-dichlorophenyl)-2,2-dichlorocyclopropane-1-carboxylicacid (C30)

Isolated as a white foam (0.6 g, 29%): ¹H NMR (400 MHz, CDCl₃) δ 7.29(d, J=0.7 Hz, 2H), 3.39 (d, J=8.2 Hz, 1H), 2.87 (d, J=8.3 Hz, 1H). ESIMSm/z 376 ([M−H]⁻).

Example 41 Preparation oftrans-2,2-dichloro-3-(3-(pentafluoro-λ⁶-sulfanyl)phenyl)cyclopropane-1-carboxylicacid (C31)

To a round-bottom flask equipped with a magnetic stir bar were addedsodium periodate (37.0 g, 0.174 mol), and water (250 mL). Nitrogen wasbubbled into the solution for 15 minutes.(3-((1R,3R)-2,2-Dichloro-3-(4-methoxyphenyl)cyclopropyl)phenyl)pentafluoro-λ⁶-sulfane(C44) (3.7 g, 0.0109 mol) was dissolved in a mixture of ethyl acetate(30 mL)/acetonitrile (30 mL) and added to the flask followed byruthenium chloride (0.150 g, 0.00067 mol). The mixture was stirred for16 hours. The mixture was diluted with dichloromethane (250 mL),filtered through Celite®, and the solid filter cake was rinsed withdichloromethane. The filtrate was transferred to a separatory funnel.The organic layer was separated and the aqueous phase was extracted withdichloromethane (4×100 mL). The combined organic layers were dried overanhydrous sodium sulfate, and concentrated under reduced pressure.Purification by reverse-phase medium performance liquid chromatography(RP-MPLC) using 10-80% acetonitrile/water as eluent afforded the titlecompound as a (2.0 g, 51%): ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J=8.5 Hz,1H), 7.65 (s, 1H), 7.51 (t, J=8.0 Hz, 1H), 7.44 (d, J=7.8 Hz, 1H), 3.55(d, J=8.3 Hz, 1H), 2.93 (d, J=8.3 Hz, 1H); ESIMS m/z 358 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 41:

trans-2,2-Dichloro-3-(4-(pentafluoro-λ⁶-sulfanyl)phenyl)cyclopropane-1-carboxylicacid (C32)

Isolated as a white powder (2.2 g): ¹H NMR (400 MHz, CDCl₃) δ 7.78 (d,J=8.7 Hz, 2H), 7.38 (d, J=8.4 Hz, 2H), 3.53 (d, J=8.3 Hz, 1H), 2.93 (d,J=8.3 Hz, 1H); ESIMS m/z 358 ([M+H]⁺).

trans-2,2-Dichloro-3-(3-iodophenyl)cyclopropane-1-carboxylic acid (C33)

Isolated as a white powder (0.700 g): ¹H NMR (400 MHz, CDCl₃) δ 7.69 (d,J=7.9 Hz, 1H), 7.62 (s, 1H), 7.29-7.21 (m, 1H), 7.12 (t, J=7.8 Hz, 1H),3.44 (d, J=8.3 Hz, 1H), 2.87 (d, J=8.3 Hz, 1H); ESIMS m/z 358 ([M+H]⁺).

trans-2,2-Dichloro-3-(4-iodophenyl)cyclopropane-1-carboxylic acid (C34)

Isolated as a white powder (1.2 g): ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d,J=8.4 Hz, 2H), 7.01 (d, J=8.2 Hz, 2H), 3.43 (d, J=8.3 Hz, 1H), 2.85 (d,J=8.3 Hz, 1H); ESIMS m/z 358 ([M+H]⁺).

trans-3-(3,5-Dichlorophenyl)-2,2-difluorocyclopropane-1-carboxylic acid(C35)

Isolated as an off-white solid (0.640 g, 44%): mp 138-142° C.; ¹H NMR(400 MHz, CDCl₃) δ 7.34 (t, J=1.9 Hz, 1H), 7.16 (d, J=1.8 Hz, 2H), 3.47(ddd, J=11.9, 7.8, 4.1 Hz, 1H), 2.75 (ddd, J=11.1, 7.9, 1.7 Hz, 1H); ¹³CNMR (101 MHz, CDCl₃) δ 170.91, 135.50, 133.88, 128.56, 126.74, 109.91(dd, J=295.1, 289.3 Hz), 32.62 (dd, J=11.3, 9.2 Hz), 32.07 (t, J=11.5Hz); ¹⁹F NMR (376 MHz, CDCl₃) δ −132.28 (d, J=152.7 Hz), −132.84 (d,J=152.8 Hz); ESIMS m/z 267 ([M−H]⁻).

Example 42 Preparation oftrans-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxylic acid(C36)

Ruthenium(III) chloride (0.080 g, 0.39 mmol) was added to a stirredmixture oftrans-1,3-dichloro-5-(-2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)benzene(C48) (2.8 g, 7.7 mmol) and sodium periodate (33 g, 160 mmol) inwater:ethyl acetate:acetonitrile (8:1:1, 155 mL) at 23° C. The resultingbiphasic brown mixture was vigorously stirred at 23° C. for 5 hours. Thereaction mixture was diluted with water (1000 mL) and extracted withdichloromethane (4×200 mL). The combined organic layers were dried overmagnesium sulfate, filtered, and concentrated. The residue was dilutedwith a sodium hydroxide solution (1 M, 100 mL) and washed with diethylether (4×50 mL). The aqueous layer was adjusted to pH 2, usingconcentrated hydrochloric acid, and extracted with dichloromethane (3×50mL). The combined organic layers were dried over magnesium sulfate,filtered, and concentrated to afford the title product as a light brownpowder (0.78 g, 34%): mp 117-120° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 13.38(br s, 1H), 7.52-7.65 (m, 3H), 3.57 (d, J=8.5 Hz, 1H), 3.50 (d, J=8.5Hz, 1H); IR (thin film) 3083 (s), 3011 (s), 1731 (s), 1590 (w), 1566(s), 1448 (w), 1431 (m), 1416 (m) cm⁻¹.

The following compounds were prepared in like manner to the procedureoutlined in Example 42:

trans-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropanecarboxylic acid(C37)

Isolated as a yellow powder (1.5 g, 39%): ¹H NMR (400 MHz, CDCl₃) δ 7.31(d, J=0.7 Hz, 2H), 3.40 (d, J=8.2 Hz, 1H), 2.86 (d, J=8.3 Hz, 1H); ¹³CNMR (101 MHz, CDCl₃) δ 171.05, 134.55, 132.44, 131.75, 128.89, 61.18,39.26, 37.14; ESIMS m/z 333 ([M−H]⁻).

trans-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropanecarboxylic acid(C38)

Isolated as a pale yellow solid (3.2 g, 51%): ¹H NMR (400 MHz, CDCl₃) δ7.47 (d, J=8.3 Hz, 1H), 7.37 (d, J=1.6 Hz, 1H), 7.12 (ddd, J=8.3, 2.1,0.6 Hz, 1H), 3.43 (d, J=8.3 Hz, 1H), 2.86 (d, J=8.3 Hz, 1H); ¹³C NMR(101 MHz, CDCl₃) δ 171.52, 132.91, 132.76, 132.29, 130.66, 130.62,128.02, 61.48, 39.65, 37.13; ESIMS m/z 298 ([M−H]⁻).

trans-2,2-Dichloro-3-(3-chloro-5-(trifluoromethyl)phenyl)cyclopropanecarboxylicacid (C39)

Isolated as an off-white solid (0.73 g, 28%): mp 113-115° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 13.39 (br s, 1H), 7.91 (s, 1H), 7.86 (s, 1H), 7.84(s, 1H), 3.69-3.60 (m, 2H); ESIMS m/z 333 ([M−H]⁻).

trans-2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropanecarboxylicacid (C40)

Isolated as an off-white solid (1.0 g, 53%): mp 121-123° C.; ¹H NMR (400MHz, DMSO-d₆) δ 13.35 (br s, 1H), 7.71 (dd, J=2.0, 7.2 Hz, 1H),7.53-7.35 (m, 2H), 3.50-3.41 (m, 2H); ESIMS m/z 281 ([M−H]⁻).

trans-2,2-Dichloro-3-(3-chloro-5-(difluoromethyl)phenyl)cyclopropane-1-carboxylicacid (C41)

Isolated as an off-white solid (2.6 g, 63%): ¹H NMR (300 MHz, CDCl₃)missing COOH signal δ 7.49 (s, 1H), 7.38 (s, 1H), 7.30 (s, 1H), 6.63 (t,J=56.0 Hz, 1H), 3.50 (d, J=8.4 Hz, 1H), 2.91 (d, J=8.0 Hz, 1H); ¹⁹F NMR(282.2 MHz, CDCl₃) δ −112.04; ESIMS m/z 313 ([M−H]⁻).

trans-2,2-Dichloro-3-(4-chloro-3-(difluoromethyl)phenyl)cyclopropane-1-carboxylicacid (C42)

Isolated as an off-white solid (6.2 g, 69%): ¹H NMR (400 MHz, CDCl₃) δ10.5 (br s, 1H), 7.55 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.34 (d, J=8.4Hz, 1H), 6.95 (t, J=54.8 Hz, 1H), 3.50 (d, J=8.4 Hz, 1H), 2.91 (d, J=8.4Hz, 1H); ¹⁹F NMR (376.2 MHz, CDCl₃) δ −115.52; ESIMS m/z 313 ([M−H]⁻).

trans-2,2-Dichloro-3-(3-(difluoromethyl)-4-fluorophenyl)cyclopropane-1-carboxylicacid (C43)

Isolated as an off-white solid (6.0 g, 77%): ¹H NMR (400 MHz, CDCl₃)missing COOH signal δ 7.49 (d, J=6.0 Hz, 1H), 7.40 (br s, 1H), 7.17 (t,J=9.2 Hz, 1H), 6.90 (t, J=54.8 Hz, 1H), 3.49 (d, J=8.0 Hz, 1H), 2.89 (d,J=8.4 Hz, 1H); ¹⁹F NMR (376.2 MHz, CDCl₃) δ −114.47, −119.69; ESIMS m/z297 ([M−H]⁻).

Example 43 Preparation oftrans-(3-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)phenyl)pentafluoro-λ⁶-sulfane(C44)

To a round-bottom flask equipped with a magnetic stir bar were added(E)-pentafluoro(3-(4-methoxystyryl)phenyl)-λ⁶-sulfane (C57) (4.13 g,0.0123 mol) and benzyl triethylammonium chloride (0.6 g, 0.00264 mol).Chloroform (150 mL) was added followed by an ice-cold aqueous solutionof sodium hydroxide (20 g, 0.5 mol) dissolved in water (34 mL). Thebiphasic mixture was stirred at 40° C. 16 hours. The reaction mixturewas cooled to 23° C., water (100 mL) was added, and the reaction mixturewas transferred to a separatory funnel. The organic layer was separatedand the aqueous phase was extracted with chloroform (2×50 mL). Thecombined organic layers were washed with brine (50 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure.Purification by flash chromatography using 0-15% ethyl acetate/hexane aseluent gave the title compound as a (3.8 g, 75%): ¹H NMR (400 MHz,CDCl₃) δ 7.75 (m, 2H), 7.58-7.46 (m, 2H), 7.30 (d, J=8.6 Hz, 2H), 6.95(d, J=8.7 Hz, 2H), 3.84 (s, 3H), 3.20 (s, 2H); ESIMS m/z 419 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 43:

trans-(4-(2,2-Dichloro-3-(4-methoxyphenyl)cyclopropyl)phenyl)pentafluoro-λ⁶-sulfane(C45)

Isolated as a white powder (4.0 g): ¹H NMR (400 MHz, CDCl₃) δ 7.75 (d,J=8.8 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H), 7.30-7.23 (m, 2H), 6.91 (d, J=8.7Hz, 2H), 3.81 (s, 3H), 3.21-3.08 (m, 2H); ESIMS m/z 419 ([M+H]⁺).trans-1-(2,2-Dichloro-3-(4-methoxyphenyl)cyclopropyl)-3-iodobenzene(C46)

Isolated as a white powder (5.7 g): ¹H NMR (400 MHz, CDCl₃) δ 7.73 (s,1H), 7.68 (d, J=7.9 Hz, 1H), 7.35 (d, J=7.7 Hz, 1H), 7.31-7.25 (m, 2H),7.13 (t, J=7.8 Hz, 1H), 6.94 (d, J=8.7 Hz, 2H), 3.84 (s, 3H), 3.13 (m,2H); ESIMS m/z 419 ([M+H]⁺).

trans-1-(2,2-Dichloro-3-(4-iodophenyl)cyclopropyl)-4-methoxybenzene(C47)

Isolated as a white powder (4.0 g): ¹H NMR (400 MHz, CDCl₃) δ 7.72 (d,J=8.4 Hz, 2H), 7.29 (m, 2H), 7.12 (d, J=8.1 Hz, 2H), 6.93 (d, J=8.8 Hz,2H), 3.83 (s, 3H), 3.11 (m, 2H); ESIMS m/z 419 ([M+H]⁺).

Example 44 Preparation oftrans-1,3-dichloro-5-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)benzene(C48)

Aqueous sodium hydroxide (50%, 6.8 mL, 130 mmol) was added to a stirredsolution of (E)-1,3-dichloro-5-(4-methoxystyryl)benzene (C61) (2.4 g,8.6 mmol) and N-benzyl-N,N-diethylethanaminium chloride (0.20 g, 0.86mmol) in chloroform (14 mL, 170 mmol) at 23° C. The resulting biphasic,dark brown mixture was vigorously stirred at 23° C. for 24 hours. Thereaction mixture was diluted with water (200 mL) and extracted withdichloromethane (2×100 mL). The combined organic layers were dried overmagnesium sulfate, filtered, and concentrated to afford the titleproduct as a brown oil (2.8 g, 90%): ¹H NMR (400 MHz, CDCl₃) δ 7.34 (t,J=1.8 Hz, 1H), 7.21-7.30 (m, 4H), 6.93 (m, 2H), 3.83 (s, 3H), 3.14 (d,J=8.5 Hz, 1H), 3.08 (d, J=8.5 Hz, 1H); IR (thin film) 3075 (w), 2934(w), 2836 (w), 1724 (w), 1640 (w), 1609 (m), 1584 (m), 1568 (s), 1513(s) cm⁻¹.

The following compounds were prepared in like manner to the procedureoutlined in Example 44:

trans-1,2,3-Trichloro-5-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)benzene(C49)

Isolated as a dark foam (4.7 g, 100%): ¹H NMR (400 MHz, CDCl₃) δ 7.40(d, J=0.6 Hz, 2H), 7.29-7.22 (m, 2H), 6.96-6.89 (m, 2H), 3.83 (s, 3H),3.12 (d, J=8.8 Hz, 1H), 3.06 (d, J=8.7 Hz, 1H); ¹³C NMR (101 MHz, CDCl₃)δ 159.46, 135.08, 134.23, 130.91, 129.85, 129.16, 125.42, 114.02, 64.67,55.32, 39.62, 38.48.

trans-1,2-Dichloro-4-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)benzene(C50)

Isolated as an orange-red oil (7.6 g, 99%): ¹H NMR (400 MHz, CDCl₃) δ7.47 (d, J=4.9 Hz, 1H), 7.45 (bs, 1H), 7.30-7.23 (m, 2H), 7.21 (dd,J=8.2, 1.9 Hz, 1H), 6.96-6.90 (m, 2H), 3.83 (s, 3H), 3.11 (app. q, J=8.8Hz, 2H); ¹³C NMR (101 MHz, CDCl₃) δ 159.39, 134.90, 132.62, 131.99,130.90, 130.40, 129.90, 128.33, 125.81, 113.98, 64.94, 55.33, 39.52,38.75.

trans-1-Chloro-3-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)-5-(difluoromethyl)benzene(C51)

Isolated as a yellow liquid (11.5 g, 69%): ¹H NMR (300 MHz, CDCl₃): δ7.47 (s, 2H), 7.39 (s, 1H), 7.28 (d, J=8.7 Hz, 2H), 6.93 (d, J=8.7 Hz,2H), 6.64 (t, J=56.1 Hz, 1H), 3.83 (s, 3H), 3.16 (q, J=8.7 Hz, 2H).

trans-1-Chloro-4-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)-2-(difluoromethyl)benzene(C52)

Isolated as a pale yellow solid (10.7 g, 83%): ¹H NMR (400 MHz, CDCl₃) δ7.65 (s, 1H), 7.46-7.41 (m, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.10-6.83 (m,3H), 3.83 (s, 3H), 3.18-3.13 (m, 2H).

trans-4-(2,2-Dichloro-3-(4-methoxyphenyl)cyclopropyl)-2-(difluoromethyl)-1-fluorobenzene(C53)

Isolated as an off-white solid (10.0 g, 55%): ESIMS m/z 374 ([M+H]⁺).

trans-1-Chloro-3-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)-5-(trifluoromethyl)benzene(C54)

Isolated as a brown solid (4.0 g, 74%): ¹H NMR (300 MHz, CDCl₃) δ 7.64(s, 1H), 7.45 (s, 1H), 7.42 (s, 1H), 7.26 (d, J=9.0 Hz, 2H), 6.93 (d,J=9.0 Hz, 1H), 3.83 (s, 3H), 3.15-3.05 (m, 2H); ESIMS m/z 395 ([M+H]⁺).

trans-2-Chloro-4-(2,2-dichloro-3-(4-methoxyphenyl)cyclopropyl)-1-fluorobenzene(C55)

Isolated as a brown liquid (2.0 g, 58%): ESIMS m/z 345 ([M+H]⁺).

Example 45 Preparation oftrans-1,3-dichloro-5-(2,2-difluoro-3-(4-methoxyphenyl)cyclopropyl)benzene(C56)

(E)-1,3-Dichloro-5-(4-methoxystyryl)benzene (C61) (1.5 g, 5.4 mmol) wasdissolved in tetrahydrofuran (10 mL) in a 25 mL microwave vial.Trimethyl(trifluoromethyl)silane (3.8 g, 26.9 mmol) and sodium iodide(0.81 g, 5.4 mmol) were added and the capped vial was heated in themicrowave at 85° C. for 1 hour. The vial was vented with a needle andanalysis of an aliquot by ¹H NMR spectroscopy indicated approximately20% conversion. Additional trimethyl(trifluoromethyl)silane (7.2 g, 54mmol) and sodium iodide (0.56 g, 3.8 mmol) were added, and the mixturewas heated in the microwave at 110° C. for 8 hours. Further analysis ofan aliquot by ¹H NMR spectroscopy indicated complete conversion withsome decomposition. The reaction mixture was partitioned between ethylacetate and saturated sodium chloride solution, the layers wereseparated, and the organic phase was dried over sodium sulfate.Filtration and concentration gave the product as a brown oil (1.8 g,100%): ¹H NMR (400 MHz, CDCl₃) δ 7.30 (t, J=1.9 Hz, 1H), 7.25-7.19 (m,4H), 6.93-6.88 (m, 2H), 3.82 (s, 3H), 2.97 (q, J=7.8 Hz, 1H), 2.88 (q,J=7.6 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −133.89; EIMS m/z 329.

Example 46 Preparation of(E)-pentafluoro(3-(4-methoxystyryl)phenyl)-λ⁶-sulfane (C57)

A flame-dried round-bottom flask equipped with a magnetic stir bar waspurged with nitrogen. Potassium tert-butoxide (0.55 g, 0.0049 mol),18-crown-6 (0.2 g, 0.00076 mol) and tetrahydrofuran (20 mL) were added.The suspension was cooled to 5° C. 3-(Pentafluorothio) benzaldehyde(0.8, 0.00345 mol) and diethyl (4-methoxybenzyl)phosphonate (1.16 g,0.00449 mol) were dissolved in tetrahydrofuran (4 mL) and added to theabove suspension over 15 minutes. The internal temperature did notexceed 8° C. during the addition. The reaction mixture was warmed to 23°C. over 30 minutes and then heated at 50° C. for 4 hours. The reactionwas concentrated under reduced pressure. Water (100 mL) and methyltert-butyl ether (MTBE; 100 mL) were added. The organic layer wasseparated and the aqueous phase was extracted with MTBE (2×75 mL). Thecombined organic layers were washed with brine (75 mL), dried overanhydrous sodium sulfate, and concentrated under reduced pressure.Purification by flash chromatography using 0-15% ethyl acetate/hexane aseluent provided the title compound as an off-white solid (0.85 g, 73%):¹H NMR (400 MHz, CDCl₃) δ 7.84 (s, 1H), 7.64-7.56 (m, 2H), 7.47 (d,J=8.7 Hz, 2H), 7.42 (t, J=8.0 Hz, 1H), 7.11 (d, J=16.3 Hz, 1H),7.02-6.86 (m, 3H), 3.84 (s, 3H); ESIMS m/z 337 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 46:

(E)-Pentafluoro(4-(4-methoxystyryl)phenyl)-λ⁶-sulfane (C58)

Isolated as a white powder (3.7 g 70%): ¹H NMR (400 MHz, CDCl₃) δ 7.71(d, J=8.8 Hz, 2H), 7.53 (d, J=8.5 Hz, 2H), 7.48 (d, J=8.7 Hz, 2H), 7.14(d, J=16.3 Hz, 1H), 7.01-6.87 (m, 3H), 3.85 (s, 3H); ESIMS m/z 337([M+H]⁺).

(E)-1-Iodo-3-(4-methoxystyryl)benzene (C59)

Isolated as a white powder (5.3 g 91%): ¹H NMR (400 MHz, CDCl₃) δ 7.85(s, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.45-7.41 (m, 3H), 7.09-7.02 (m, 2H),6.91 (d, J=8.8 Hz, 2H), 6.85 (d, J=16.3 Hz, 1H), 3.84 (s, 3H); ESIMS m/z337 ([M+H]⁺).

(E)-1-Iiodo-4-(4-methoxystyryl)benzene (C60)

Isolated as a white powder (3.3 g 94%): ¹H NMR (400 MHz, CDCl₃) δ 7.66(d, J=8.4 Hz, 2H), 7.44 (d, J=8.7 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.06(d, J=16.3 Hz, 1H), 6.94-6.83 (m, 3H), 3.83 (s, 3H); ESIMS m/z 337([M+H]⁺).

Example 47 Preparation of (E)-1,3-dichloro-5-(4-methoxystyryl)benzene(C61)

Sodium methoxide powder (98%, 0.63 g, 11 mmol) was added to a stirredsolution of 3,5-dichlorobenzaldehyde (2.0 g, 11 mmol) and diethyl4-methoxybenzylphosphonate (2.0 mL, 11 mmol) in dryN,N-dimethylformamide (38 mL) at 23° C. The resulting heterogeneous darkblue mixture was heated to 80° C., resulting in a dark brown mixture,and stirred for 24 hours. The cooled reaction mixture was diluted withwater (500 mL) and extracted with diethyl ether (3×100 mL). The combinedorganic layers were diluted with hexane (150 mL) and washed with water(300 mL). The organic layer was dried over magnesium sulfate, filtered,and concentrated to afford the title product as a light brown oil (2.4g, 75%): ¹H NMR (400 MHz, CDCl₃) δ 7.44 (m, 2H), 7.34 (d, J=2 Hz, 2H),7.20 (t, J=2 Hz, 1H), 7.06 (d, J=16.5 Hz, 1H), 6.91 (m, 2H), 6.82 (d,J=16.5 Hz, 1H), 3.84 (s, 3H); IR (thin film) 2934 (w), 2835 (w), 1724(w), 1637 (w), 1605 (m), 1581 (m), 1558 (m), 1511 (s) cm⁻¹.

The following compounds were prepared in like manner to the procedureoutlined in Example 47:

(E)-1,2,3-Trichloro-5-(4-methoxystyryl)benzene (C62)

Isolated as an off-white solid (3.7 g, 31%): ¹H NMR (400 MHz, CDCl₃) δ7.49-7.46 (m, 2H), 7.47-7.39 (m, 2H), 7.04 (d, J=16.3 Hz, 1H), 6.93-6.89(m, 2H), 6.78 (d, J=16.3 Hz, 1H), 3.84 (s, 3H); ¹³C NMR (101 MHz, CDCl₃)δ 159.46, 135.08, 134.23, 130.91, 129.85, 129.16, 125.42, 114.02, 64.67,55.32, 39.62, 38.48; EIMS m/z 313 ([M]⁺).

(E)-1,2-Dichloro-4-(4-methoxystyryl)benzene (C63)

Isolated as an off-white solid (6.0 g, 53%): mp 91-94° C.; ¹H NMR (400MHz, CDCl₃) δ 7.56 (d, J=2.0 Hz, 1H), 7.46-7.42 (m, 2H), 7.39 (d, J=8.4Hz, 1H), 7.29 (dd, J=8.4, 2.1 Hz, 1H), 7.04 (d, J=16.2 Hz, 1H),6.93-6.88 (m, 2H), 6.85 (d, J=16.3 Hz, 1H), 3.84 (s, 3H); ¹³C NMR (101MHz, CDCl₃) δ 159.75, 137.86, 132.72, 130.58, 130.49, 130.12, 129.33,127.96, 127.77, 125.37, 123.98, 114.24, 55.35; EIMS m/z 279 ([M]+).

(E)-1-Chloro-3-(4-methoxystyryl)-5-(trifluoromethyl)benzene (C64)

Isolated as an off-white solid (4.3 g, 58%): ¹H NMR (300 MHz, CDCl₃) δ7.62 (s, 1H), 7.58 (s, 1H), 7.48-7.42 (m, 3H), 7.12 (d, J=16.2 Hz, 1H),6.95-6.85(m, 3H), 3.84 (s, 3H); ESIMS m/z 313 ([M+H]⁺).

(E)-2-Bromo-1,3-dichloro-5-(4-methoxystyryl)benzene (C65)

Isolated as an off-white solid (2.8 g, 40%): ¹H NMR (300 MHz, CDCl₃) δ7.46 (s, 2H), 7.43 (d, J=9.0 Hz, 2H), 7.07 (d, J=13.5 Hz, 1H), 6.90 (d,J=9.0 Hz, 1H), 6.73 (d, J=13.5 Hz, 1H), 3.84 (s, 3H); ESIMS m/z 358([M+H]⁺).

(E)-2-Chloro-1-fluoro-4-(4-methoxystyryl)benzene (C66)

Isolated as an off-white solid (6.0 g, 72%): ESIMS m/z 263 ([M+H]⁺).

Example 48 Preparation of(E)-1,3-dichloro-2-fluoro-5-(4-methoxystyryl)benzene (C67)

A stirred mixture of 5-bromo-1,3-dichloro-2-fluorobenzene (2.00 g, 8.20mmol), 1-methoxy-4-vinylbenzene (1.32 g, 9.80 mmol), and triethylamine(20 mL) under argon was degassed for 5 minutes. Palladium(II) acetate(0.0368 g, 0.164 mmol) and 1,1′-bis(diphenylphosphino)ferrocene (0.181g, 0.328 mmol) were added and the reaction was heated to 90° C. for 16hours. The reaction mixture was poured into water and extracted withethyl acetate. The combined organic layers were dried over sodiumsulfate, filtered, and concentrated. Purification by flash columnchromatography provided the title compound as an off-white solid (1.60g, 67%): ¹H NMR (300 MHz, CDCl₃) δ 7.41 (d, J=8.8 Hz, 2H), 7.31 (s, 1H),7.37 (s, 1H), 6.96 (d, J=16.0 Hz, 1H), 6.89 (d, J=8.8 Hz, 2H), 6.76 (d,J=16.0 Hz, 1H), 3.84 (s, 3H); ESIMS m/z 297 ([M+H]⁺).

Example 49 Preparation of (E)-3-chloro-5-(4-methoxystyryl)benzaldehyde(C68)

To a stirred solution of 3-bromo-5-chlorobenzaldehyde (20.0 g, 91.32mmol) in dimethylacetamide, 1-methoxy-4-vinylbenzene (18.3 g, 136.9mmol) and triethylamine (50 mL, 273.96 mmol) were added, and thereaction mixture was degassed with argon for 5 minutes. Palladium(II)acetate (410 mg, 1.83 mmol) and tri-o-tolylphosphine (1.11 g, 3.65 mmol)were added, and the resulting reaction mixture was heated to 100° C. for16 hours. The reaction mixture was poured into water and extracted withethyl acetate. The combined organic layer was dried over sodium sulfateand concentrated under reduced pressure. The resulting crude materialwas purified by flash column chromatography using 5-10% ethyl acetate inpetroleum ether as the eluent to afford the title compound as a yellowsolid (13.5 g, 54%): ¹H NMR (300 MHz, CDCl₃) δ 9.99 (s, 1H), 7.85 (s,1H), 7.69 (s, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.16 (d, J=16.2 Hz, 1H), 6.94(t, J=8.4 Hz, 3H), 3.84 (s, 3H); ESIMS m/z 273 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 49:

(E)-2-Chloro-5-(4-methoxystyryl)benzaldehyde (C69)

Isolated as a pale yellow solid (11.8 g, 27%): ¹H NMR (300 MHz, CDCl₃) δ10.45 (s, 1H), 8.02 (s, 1H), 7.62 (d, J=6.4 Hz, 1H), 7.46-7.40 (m, 3H),7.12 (d, J=16.4 Hz, 1H), 6.95-6.90 (m, 3H), 3.95 (s, 3H); ESIMS m/z 273([M+H]⁺).

(E)-2-Fluoro-5-(4-methoxystyryl)benzaldehyde (C70)

Isolated as an off-white solid (0.25 g, 20%): ¹H NMR (400 MHz, CDCl₃) δ10.43 (s, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.54-7.46 (m, 4H), 7.20 (d,J=16.0 Hz, 1H), 6.94-6.90 (m, 3H), 3.85 (s, 3H); ESIMS m/z 274 ([M+H]⁺).

Example 50 Preparation of(E)-1-chloro-3-(difluoromethyl)-5-(4-methoxy-styryl)benzene (C71)

To a stirred solution of (E)-3-chloro-5-(4-methoxystyryl) benzaldehyde(C68) (13 g, 47.79 mmol) in dichloromethane (130 mL) was addeddiethylaminosulfur trifluoride (31.5 mL, 238.97 mmol) at −78° C. Theresulting solution was stirred for 20 hours at room temperature. Thereaction mixture was cooled to 0° C., and a solution of saturatedaqueous sodium bicarbonate was added dropwise. The layers were separatedand the aqueous layer was extracted with dichloromethane (3×75 mL). Thecombined organic layer was washed with water and brine, dried oversodium sulfate, and concentrated. The crude material was purified byflash column chromatography using 10-20% ethyl acetate in hexanes as theeluent to afford the title compound as a pale yellow oil (13.1 g, 94%):¹H NMR (400 MHz, CDCl₃) δ 7.55 (s, 1H), 7.45 (d, J=8.8 Hz, 3H), 7.34 (s,1H), 7.10 (d, J=16 Hz, 1H), 6.90 (t, J=8.4 Hz, 3H), 6.61 (t, J=56.4 Hz,1H), 3.80 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −111.72.

The following compounds were prepared in like manner to the procedureoutlined in Example 50:

(E)-1-Chloro-2-(difluoromethyl)-4-(4-methoxystyryl)benzene (C72)

Isolated as an off-white solid (12 g, 94%): ¹H NMR (300 MHz, CDCl₃) δ7.75 (s, 1H), 7.51-7.44 (m, 3H), 7.37 (d, J=8.4 Hz, 1H), 7.13 (d, J=6.6Hz, 1H), 7.06 (s, 1H), 6.95-6.89 (m, 3H), 3.95(s, 3H); ¹⁹F NMR (282 MHz,CDCl₃) δ −115.31; ESIMS m/z 295 ([M+H]⁺).

(E)-2-(Difluoromethyl)-1-fluoro-4-(4-methoxystyryl)benzene (C73)

Isolated as an off-white solid (14.0 g, 70%): ¹H NMR (300 MHz, CDCl₃) δ7.69 (d, J=9.0 Hz, 1H), 7.57-7.53 (m, 1H), 7.45 (d, J=9.9 Hz, 2H),7.13-7.06 (m, 2H), 7.00-6.89 (m, 4H), 3.85 (s, 3H); ESIMS m/z 279([M+H]⁺).

Example 51 Preparation oftrans-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane carboxylic acid(C36)

Sodium permanganate (40% aqueous) (84 g, 236 mmol) was added dropwise toa stirred mixture oftrans-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carbaldehyde(C79) (58.7 g, 196 mmol) in acetone (982 mL) at 15° C. The resultingmixture was stirred at 20° C. for 2 hours. The reaction mixture wasdiluted with isopropyl alcohol (20 mL) and concentrated to remove theacetone. Celite® and aqueous hydrochloric acid (1 N, 295 mL, 295 mmol)were added to the brown residue. The resulting mixture was diluted withethyl acetate (500 mL) and filtered through Celite®. The filtrate waswashed with brine (200 mL). The organic layer was dried over sodiumsulfate, filtered and concentrated. The resulting slurry was dilutedwith heptane (˜200 mL) and allowed to solidify at 20° C. The solid wascollected, washed with heptane and dried to afford the title product asa white solid (54.68 g, 91%): ¹H NMR (300 MHz, CDCl₃) δ 7.36 (t, J=1.9Hz, 1H), 7.17 (dd, J=1.9, 0.7 Hz, 2H), 3.48-3.37 (m, 1H), 2.87 (d, J=8.3Hz, 1H); ¹³C NMR (400 MHz, CDCl₃) δ 135.44, 135.28, 128.66, 127.30,39.68, 36.88; ESIMS m/z=298.9 ([M−H])⁻.

The following compounds were prepared in like manner to the procedureoutlined in Example 51:

trans-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxylicacid (C37)

Isolated as a white solid (2.78 g, 95%): ¹H NMR (400 MHz, DMSO-d₆) δ13.41 (s, 1H), 7.81 (d, J=0.6 Hz, 2H), 3.62 (d, J=8.6 Hz, 1H), 3.52 (d,J=8.6 Hz, 1H); ESIMS m/z 332 ([M−H]⁻).

trans-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxylic acid(C38)

Isolated as a white solid (124 g, 82%): mp 133-135° C.: ¹H NMR (500 MHz,DMSO-d₆) δ 13.39 (s, 1H), 7.76 (d, J=2.0 Hz, 1H), 7.64 (d, J=8.3 Hz,1H), 7.44 (dd, J=8.4, 2.1 Hz, 1H), 3.49 (s, 2H). ¹³C NMR (126 MHz,DMSO-d₆) δ 166.34, 133.35, 130.47, 130.33, 130.09, 129.77, 128.81,61.43, 37.00, 36.06.

trans-2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxylicacid (C40)

Isolated as a white solid (165 g, 71%): ¹H NMR (400 MHz, CDCl₃) δ 11.57(s, 1H), 7.42 (dd, J=8.2, 7.6 Hz, 1H), 7.11-6.98 (m, 2H), 3.46 (d, J=8.2Hz, 1H), 2.85 (d, J=8.3 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −114.07;ESIMS m/z 282 ([M−H]⁻).

In another preparation, isolated as a white powder (10.385 g, 77%):119-121° C.; ¹H NMR (400 MHz, CDCl₃) δ 11.83 (s, 1H), 7.32 (d, J=6.9 Hz,1H), 7.16 (d, J=6.7 Hz, 2H), 3.45 (d, J=8.3 Hz, 1H), 2.85 (d, J=8.3 Hz,1H); ¹³C NMR (101 MHz, CDCl₃) δ 172.18, 159.26, 156.77, 130.95, 129.26,129.22, 128.57, 128.50, 121.52, 121.34, 116.94, 116.73, 61.59, 39.64,37.30; ¹⁹F NMR (376 MHz, CDCl₃) δ −115.16; ESIMS m/z 281 [(M−H]⁻).

trans-3-(4-Bromo-3-(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylicacid (C74)

Isolated as a white solid (1.21 g, 51%): ¹H NMR (400 MHz, CDCl₃) δ 10.87(s, 1H), 7.74 (d, J=8.3 Hz, 1H), 7.58 (d, J=2.2 Hz, 1H), 7.30 (dd,J=8.3, 2.2 Hz, 1H), 3.49 (d, J=8.3 Hz, 1H), 2.91 (d, J=8.3 Hz, 1H); ¹⁹FNMR (376 MHz, CDCl₃) δ −62.77, −62.78; ESIMS m/z 377 ([M−H]⁻).

trans-2,2-Dichloro-3-(4-chloro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (C75)

Isolated as a white solid (2.02 g, 43%): ¹H NMR (400 MHz, CDCl₃) δ7.96-7.51 (m, 3H), 7.39 (dd, J=8.3, 2.2 Hz, 1H), 3.50 (d, J=8.3 Hz, 1H),2.90 (d, J=8.3 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −62.75, −62.75; ESIMSm/z 332 ([M−H]⁻).

trans-2,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (C76)

Isolated as a white solid (3.08 g, 67%): ¹H NMR (400 MHz, CDCl₃) δ 8.18(s, 1H), 7.64-7.39 (m, 2H), 7.24 (t, J=9.3 Hz, 1H), 3.50 (dd, J=8.4, 1.0Hz, 1H), 2.89 (d, J=8.3 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −61.48,−61.51, −114.23, −114.26, −114.29; ESIMS m/z 316 ([M−H]⁻).

trans-2,2-Dichloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (C77)

Isolated as a white solid (3.7 g, 55%): ¹H NMR (400 MHz, CDCl₃) δ 11.40(s, 1H), 7.42-7.27 (m, 2H), 7.20 (dt, J=8.9, 2.0 Hz, 1H), 3.53 (d, J=8.3Hz, 1H), 2.93 (d, J=8.3 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −62.86,−109.49; ESIMS m/z 316 ([M−H]⁻).

trans-3-(3-Bromo-5-(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxylicacid (C78)

Isolated as a tan solid (0.375 g, 31%): ¹H NMR (400 MHz, CDCl₃) δ 10.52(s, 1H), 7.77 (s, 1H), 7.62 (d, J=1.8 Hz, 1H), 7.46 (s, 1H), 3.52 (d,J=8.2 Hz, 1H), 2.93 (d, J=8.3 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ−62.84; ESIMS m/z 377 ([M−H]⁻).

Example 52 Preparation oftrans-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carbaldehyde(C79)

Aqueous hydrochloric acid (2 N, 237 mL) was added to a stirred solutionof1,3-dichloro-5-((trans-2,2-dichloro-3-(diethoxymethyl)cyclopropyl)benzene(C83) (85.7 g, 227 mmol) in acetonitrile (1184 mL). The mixture wasstirred at 20° C. for 16 hours. The resulting mixture was diluted withwater (200 mL) and concentrated to remove the acetonitrile. Theresulting aqueous mixture was extracted with hexanes (600 mL). Theorganic layer was washed water (300 mL), dried over anhydrous sodiumsulfate, filtered and concentrated. The crude product was purified byflash column chromatography using 0-20% ethyl acetate/hexanes as eluentto afford the title product as a yellow oil (58.7 g, 86%, purity 95%):¹H NMR (400 MHz, CDCl₃) δ 9.54 (d, J=4.0 Hz, 1H), 7.46-7.09 (m, 3H),3.51 (d, J=8.0 Hz, 1H), 2.92 (dd, J=8.0, 4.0 Hz, 1H); ¹³C NMR (126 MHz,CDCl₃) δ 193.41, 135.33, 135.09, 128.78, 127.34, 42.89, 39.31; IR (thinfilm) 3078, 2847, 1714, 1590, 1566, 1417, 1387.

The following compounds were prepared in like manner to the procedureoutlined in Example 52:

trans-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carbaldehyde(C80)

Isolated as orange oil (143 g, 98%): ¹H NMR (400 MHz, CDCl₃) δ 9.53 (d,J=4.1 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.37 (dd, J=2.2, 0.7 Hz, 1H),7.12 (ddd, J=8.3, 2.2, 0.7 Hz, 1H), 3.51 (dd, J=7.9, 0.8 Hz, 1H), 2.90(dd, J=8.0, 4.1 Hz, 1H).

trans-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carbaldehyde(C81)

Isolated as a yellow solid (2.8 g, 69%): ¹H NMR (400 MHz, CDCl₃) δ 9.55(d, J=3.9 Hz, 1H), 7.30 (d, J=0.7 Hz, 2H), 3.48 (dt, J=8.0, 0.8 Hz, 1H),2.92 (dd, J=7.9, 3.9 Hz, 1H).

trans-2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carbaldehyde(C82)

Isolated as orange oil (230 g, 97%): ¹H NMR (300 MHz, CDCl₃) δ 9.52 (d,J=4.2 Hz, 1H), 7.36-7.30 (m, 1H), 7.19-7.16 (m, 1H), 7.15 (d, J=1.2 Hz,1H), 3.51 (dt, J=7.9, 0.7 Hz, 1H), 2.88 (dd, J=7.9, 4.2 Hz, 1H).

In another preparation, isolated as a yellow oil (12.496 g, 71%): ¹H NMR(400 MHz, CDCl₃) δ 9.52 (d, J=4.1 Hz, 1H), 7.33 (d, J=7.2 Hz, 1H), 7.16(dd, J=6.8, 1.0 Hz, 2H), 3.53 (d, J=7.9 Hz, 1H), 2.90 (dd, J=7.9, 4.1Hz, 1H); ¹³C NMR (101 MHz, CDCl₃) δ 193.77, 159.27, 156.78, 131.03,129.04, 129.00, 128.66, 128.59, 121.49, 121.31, 116.95, 116.74, 61.68,43.10, 39.25; ¹⁹F NMR (376 MHz, CDCl₃) δ −115.01; EIMS m/z 266.

Example 53 Preparation of1,3-dichloro-5-(trans-2,2-dichloro-3-(diethoxy-methyl)cyclopropyl)benzene(C83)

A 1 L 4-neck flask equipped with a mechanical stirrer, condenser,temperature probe and nitrogen inlet was charged with(E)-1,3-dichloro-5-(3,3-diethoxyprop-1-en-1-yl)benzene (C87) (40 g, 138mmol) and CHCl₃ (447 mL). Tetrabutylammonium hexafluorophosphate(V)(1.081 g, 2.76 mmol) was added. The light yellow solution was heated to45° C. With vigorous stirring (˜400 rpm), aqueous sodium hydroxide (50%,182 mL) was added dropwise via addition funnel (over 1 hour). After 20hours, the mixture was allowed to cool. The mixture was diluted withhexane (200 mL). The organic top layer was decanted (off the aqueouslower suspension) through Celite®, washing the filtercake with hexane(200 mL). The filtrate was washed with brine (˜200 mL), dried oversodium sulfate, filtered and concentrated to provide the title compoundas a brown oil (50.2 g, 97%, purity 95%): ¹H NMR (300 MHz, CDCl₃) δ 7.31(t, J=1.9 Hz, 1H), 7.15 (dd, J=1.9, 0.7 Hz, 2H), 4.59 (d, J=6.2 Hz, 1H),3.80-3.57 (m, 4H), 2.77 (d, J=8.5 Hz, 1H), 2.25 (dd, J=8.5, 6.2 Hz, 1H),1.30 (t, J=7.0 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H).

The following compounds were prepared in like manner to the procedureoutlined in Example 53:

1,2-Dichloro-4-(trans-2,2-dichloro-3-(diethoxymethyl)cyclopropyl)benzene(C84)

Isolated as a brown oil (184 g, 99%): ¹H NMR (400 MHz, CDCl₃) δ 7.43 (d,J=8.2 Hz, 1H), 7.36 (dd, J=2.2, 0.7 Hz, 1H), 7.10 (ddd, J=8.3, 2.1, 0.7Hz, 1H), 4.59 (d, J=6.2 Hz, 1H), 3.82-3.55 (m, 4H), 2.77 (d, J=8.5 Hz,1H), 2.24 (dd, J=8.5, 6.3 Hz, 1H), 1.30 (t, J=7.0 Hz, 3H), 1.20 (t,J=7.1 Hz, 3H).

1,2,3-Trichloro-5-(trans-2,2-dichloro-3-(diethoxymethyl)cyclopropyl)benzene(C85)

Isolated as a brown oil (146 g, 93%): ¹H NMR (400 MHz, CDCl₃) δ 7.29 (d,J=0.7 Hz, 2H), 4.59 (d, J=6.1 Hz, 1H), 3.82-3.54 (m, 4H), 2.75 (d, J=8.5Hz, 1H), 2.23 (dd, J=8.5, 6.1 Hz, 1H), 1.30 (t, J=7.0 Hz, 3H), 1.20 (t,J=7.0 Hz, 3H).

2-Chloro-4-(trans-2,2-dichloro-3-(diethoxymethyl)cyclopropyl)-1-fluoro-benzene(C86)

Isolated as a brown oil (63 g, 96%): ¹H NMR (400 MHz, CDCl₃) δ 7.44 (dd,J=7.0, 2.2 Hz, 1H), 7.29-7.22 (m, 1H), 7.09 (t, J=8.7 Hz, 1H), 6.62 (dd,J=16.1, 1.2 Hz, 1H), 6.14 (dd, J=16.1, 5.0 Hz, 1H), 5.05 (dd, J=4.9, 1.2Hz, 1H), 3.70 (dq, J=9.3, 7.0 Hz, 2H), 3.56 (dq, J=9.4, 7.1 Hz, 2H),1.25 (t, J=7.1 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 158.91, 156.42,133.65, 133.62, 130.47, 128.65, 128.07, 128.05, 126.39, 126.32, 121.26,121.08, 116.72, 116.51, 100.93, 61.17, 15.24; ¹⁹F NMR (376 MHz, CDCl₃) δ−116.36.

In another preparation, isolated as an amber oil (22.38 g, 88%): ¹H NMR(400 MHz, CDCl₃) δ 7.31 (m, 1H), 7.13 (m, 2H), 4.59 (d, J=6.3 Hz, 1H),3.69 (m, 4H), 2.78 (d, J=8.5 Hz, 1H), 2.23 (dd, J=8.5, 6.3 Hz, 1H), 1.30(t, J=7.1 Hz, 3H), 1.20 (t, J=7.1 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ−116.48; EIMS m/z 295 [M−OEt].

Example 54 Preparation of(E)-1,3-dichloro-5-(3,3-diethoxyprop-1-en-1-yl)benzene (C87)

Step 1a: Acetaldehyde (120 g, 2688 mmol) was added to a stirred mixtureof 3,5-dichlorobenzaldehyde (96 g, 538 mmol) in toluene (400 mL) at 0°C. A solution of potassium hydroxide (3.35 g, 53.8 mmol) in methylalcohol (10 mL) was added dropwise via addition funnel. The resultingmixture was stirred at 0° C. for 4 hours until all of the3,5-dichlorobenzaldehyde was consumed by thin layer chromatography. Step1b: Ethyl acetate (500 mL) and concentrated hydrochloric acid (37%aqueous, 44.1 mL, 538 mmol) were added to the reaction mixture. Theresulting mixture was heated at 80° C., and a colorless liquid wasallowed to distill (200 mL). The reaction mixture was diluted with water(500 mL) and extracted with ethyl acetate. The organic layer was washedwith brine, dried over sodium sulfate, filtered, and concentrated toafford (E)-3-(3,5-dichlorophenyl) acrylaldehyde as a light yellow solid(115 g) which was used directly without further purification: ¹H NMR(300 MHz, CDCl₃) δ 9.72 (dd, J=7.4, 0.5 Hz, 1H), 7.43 (q, J=1.8 Hz, 3H),7.35 (d, J=16.0 Hz, 1H), 6.69 (dd, J=16.0, 7.4 Hz, 1H).

Step 2: Triethoxymethane (31.4 g, 208 mmol) and pyridin-1-ium4-methylbenzenesulfonate (0.528 g, 2.079 mmol) were added to a stirredsolution of (E)-3-(3,5-dichlorophenyl) acrylaldehyde (44 g, 208 mmol) inethanol (416 mL). The resulting mixture was stirred at 20° C. for 20hours. A solution of saturated aqueous sodium carbonate (50 mL) wasadded to the reaction mixture. The resulting mixture was concentrated at45° C. to remove the ethanol. The concentrate was diluted with water andextracted with hexane. The organic layer was washed with brine, driedover sodium sulfate, filtered and concentrated to afford the titleproduct as a light yellow oil (56.13 g, 93%): ¹H NMR (400 MHz, CDCl₃) δ7.25 (dt, J=10.6, 1.9 Hz, 3H), 6.61 (dd, J=16.1, 1.1 Hz, 1H), 6.22 (dd,J=16.1, 4.7 Hz, 1H), 5.17 (s, 1H), 5.14-5.00 (m, 1H), 3.78-3.49 (m, 4H),1.24 (q, J=7.2 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 139.34, 135.14,130.27, 129.88, 127.71, 125.08, 100.60, 61.20, 15.25.

The following compounds were prepared in like manner to the procedureoutlined in Example 54:

(E)-1,2-Dichloro-4-(3,3-diethoxyprop-1-en-1-yl)benzene (C88)

Isolated as an orange oil (142 g, 91%): ¹H NMR (300 MHz, CDCl₃) δ 7.48(d, J=2.0 Hz, 1H), 7.39 (dd, J=8.3, 0.8 Hz, 1H), 6.62 (d, J=16.1 Hz,1H), 6.20 (ddd, J=16.1, 4.9, 0.8 Hz, 1H), 5.06 (dt, J=4.9, 1.0 Hz, 1H),3.78-3.48 (m, 4H), 1.25 (td, J=7.1, 0.8 Hz, 6H).

(E)-1,2,3-Trichloro-5-(3,3-diethoxyprop-1-en-1-yl)benzene (C89)

Isolated as an orange oil (40 g, 91%): ¹H NMR (400 MHz, CDCl₃) δ 7.41(s, 2H), 6.58 (dd, J=16.1, 1.2 Hz, 1H), 6.21 (dd, J=16.1, 4.6 Hz, 1H),5.06 (dd, J=4.7, 1.2 Hz, 1H), 3.69 (dq, J=9.3, 7.1 Hz, 2H), 3.55 (dq,J=9.5, 7.0 Hz, 2H), 1.25 (t, J=7.1 Hz, 6H).

(E)-2-Chloro-4-(3,3-diethoxyprop-1-en-1-yl)-1-fluorobenzene (C90)

Isolated as an orange oil (283 g, 84%): ¹H NMR (400 MHz, CDCl₃) δ 7.44(dd, J=7.0, 2.2 Hz, 1H), 7.29-7.22 (m, 1H), 7.09 (t, J=8.7 Hz, 1H), 6.62(dd, J=16.1, 1.2 Hz, 1H), 6.14 (dd, J=16.1, 5.0 Hz, 1H), 5.05 (dd,J=4.9, 1.2 Hz, 1H), 3.70 (dq, J=9.3, 7.0 Hz, 2H), 3.56 (dq, J=9.4, 7.1Hz, 2H), 1.25 (t, J=7.1 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃) δ 158.91,156.42, 133.65, 133.62, 130.47, 128.65, 128.07, 128.05, 126.39, 126.32,121.26, 121.08, 116.72, 116.51, 100.93, 61.17, 15.24; ¹⁹F NMR (376 MHz,CDCl₃) δ −116.36.

In another preparation, isolated as a colorless oil (16.75 g, 64%): ¹HNMR (400 MHz, CDCl₃) δ 7.43 (dd, J=7.0, 2.2 Hz, 1H), 7.25 (m, 1H), 7.07(t, J=8.7 Hz, 1H), 6.62 (d, J=16.1 Hz, 1H), 6.13 (dd, J=16.1, 4.9 Hz,1H), 5.05 (dd, J=4.9, 1.0 Hz, 1H), 3.70 (dq, J=9.4, 7.1 Hz, 2H), 3.56(dq, J=9.4, 7.0 Hz, 2H), 1.25 t, J=7.1 Hz, 6H); ¹³C NMR (101 MHz, CDCl₃)δ 158.91, 156.42, 133.65, 133.62, 130.47, 128.65, 128.07, 128.05,126.39, 126.32, 121.26, 121.08, 116.72, 116.51, 100.93, 61.17, 15.24;¹⁹F NMR (376 MHz, CDCl₃) δ −116.36; EIMS m/z 258.

Example 55 Preparation of(1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylicacid (C91)

1^(st) resolution: (R)-1-Phenylethanamine (6.49 g, 53.0 mmol) was slowlyadded to a stirred solution ofrac-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-carboxylic acid)(32.45 g, 106 mmol) in acetone (106 mL). The resulting solution wasstirred at 45° C. After a solid began to deposit, the mixture was placedat 5° C. for 4 hours. The solid was collected, washed with minimal coldacetone and dried. The white solid salt was diluted with ethyl acetate(100 mL) and washed with aqueous hydrochloric acid (1 N, 10 mL) andbrine (30 mL). The organic layer was dried over sodium sulfate, filteredand concentrated to afford the title product as a white solid (10.33 g,88% enantiomeric excess “ee”).

2^(nd) resolution: (R)-1-Phenylethanamine (3.4 g, 28 mmol) was slowlyadded to a stirred solution ofrac-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-carboxylic acid)(10.33 g, 88% ee) in acetone (100 mL). After 2 hours, a solid wascollected, washed with minimal cold acetone and dried. The solid wastreated with aqueous hydrochloric acid to afford the title compound as awhite solid (7.84 g, 97% ee, 24.2%): Specific Rotation: +47.4 (10 mg/mLin acetonitrile, 589 nm, 25.2° C.); ¹H NMR (300 MHz, CDCl₃) δ 7.36 (t,J=1.9 Hz, 1H), 7.17 (dd, J=1.9, 0.7 Hz, 2H), 3.48-3.37 (m, 1H), 2.87 (d,J=8.3 Hz, 1H); ¹³C NMR (400 MHz, DMSO-d₆) δ 166.28, 136.40, 133.39,127.27, 127.04, 61.36, 37.10, 35.98; ESIMS m/z 298.9 ([M−H]⁻).

Enantiomeric excess values (ee %) was determined by Chiral HPLC methodas follows: Column: CHIRALPAK© ZWIX(+), particle size 3 μm, dimension 3mm×150 mm, DAIC 511584; Mobile phase which is a mixture of 500 mLacetonitrile, 500 mL methanol, 20 mL water, 1.9 mL formic acid, and 2.6mL diethylamine; Flow rate: 0.5 mL/min; Time: 9 min; Temperature: 25° C.

The following compounds were prepared in like manner to the procedureoutlined in Example 55:

(1R,3R)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxylicacid (C92)

Isolated as a white solid (6.7 g, 30%, 96% ee). Analytical data areconsistent with racemic acid C38.

(1R,3R)-2,2-Dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxylicacid (C93)

Isolated as a white solid (0.5 g, 13%, 99% ee). Analytical data areconsistent with racemic acid C40.

(1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxylicacid (C94)

Isolated as a white solid (2 g, 29%, 99% ee). Analytical data areconsistent with racemic acid C37.

(1R,3R)-2,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (C95)

Isolated as a clear colorless oil (0.11 g, 14%, 80% ee). Analytical dataare consistent with racemic acid C76.

Example 56 Preparation of 3,4,5-trichlorobenzaldehyde (C96)

In an oven dried, nitrogen flushed, 500 mL round-bottomed flask equippedwith a pressure equalizing addition funnel,5-bromo-1,2,3-trichlorobenzene (10.0 g, 38.4 mmol) was dissolved intetrahydrofuran (100 mL), and the resulting solution was cooled in anice bath under nitrogen. isoPropyl magnesium chloride (2 M solutiontetrahydrofuran, 21.1 mL, 42.3 mmol) was added dropwise with goodstirring over 15 minutes via the addition funnel. After 0.5 hours,N,N-dimethylformamide (3.72 mL, 48.0 mmol) was added to the darksolution with stirring. After an additional 0.5 hours, hydrochloric acid(1 N, 100 mL) was added with stirring. The layers were separated, andthe organic layer was washed with brine. The combined aqueous layerswere extracted with ether, and the combined organics were dried oversodium sulfate, filtered, and concentrated to afford the title compoundas a white solid (10:1 mixture of title compound to1,2,3-trichlorobenzene, 7.96 g, 99%): ¹H NMR (CDCl₃) δ 9.91 (s, 1H),7.88 (s, 2H); EIMS m/z 209 ([M]⁺).

Example 57 Preparation of5-amino-2-cyano-N-(2,4-difluorophenyl)-N-methylbenzamide (C97)

To a solution of2-cyano-N-(2,4-difluorophenyl)-N-methyl-5-nitrobenzamide (C138) (0.051g, 0.16 mmol) in methanol (1.5 mL) and water (0.5 mL) was added ironpowder (0.045 g, 0.80 mmol) and ammonium chloride (0.026 g, 0.48 mmol).The reaction mixture was heated at 60° C. for 2 hours. The reactionmixture was filtered through Celite®, and the filtrate was diluted withethyl acetate and washed with water. The combined organic phases weredried over magnesium sulfate, filtered, and concentrated to provide thetitle compound as a colorless oil (0.054 g, 99%): Major isomer—¹H NMR(500 MHz, CDCl₃) δ 7.37 (td, J=8.8, 5.8 Hz, 1H), 7.22 (d, J=8.5 Hz, 1H),6.82-6.70 (m, 2H), 6.53 (t, J=1.9 Hz, 1H), 6.47 (dd, J=8.5, 2.4 Hz, 1H),4.27 (s, 2H), 3.41 (s, 3H); ¹⁹F NMR (471 MHz, CDCl₃) δ −107.99 (p, J=7.8Hz), −115.44 (q, J=8.8 Hz); ESIMS m/z 288 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 57:

Preparation of 5-amino-2-chloro-N-(4-fluorophenyl)benzamide (C98)

Isolated as a white solid (1.75 g, 54%).

5-Amino-2-chloro-N-(2,4-difluorophenyl)benzamide (C99)

Isolated as a purple solid (0.37 g, 28%): ¹H NMR (400 MHz, CDCl₃) δ 8.42(tdd, J=9.7, 6.0, 3.6 Hz, 1H), 8.25 (s, 1H), 7.21 (d, J=8.5 Hz, 1H),7.13 (d, J=2.9 Hz, 1H), 6.97-6.88 (m, 2H), 6.73 (dd, J=8.5, 2.9 Hz, 1H),3.84 (s, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −114.57 (d, J=4.6 Hz), −125.78(d, J=4.6 Hz); ESIMS m/z 283 ([M+H]⁺).

N-Allyl-5-amino-2-chloro-N-(2-cyano-4-fluorophenyl)benzamide (C100)

A mixture of amide rotamers was isolated as a gold oil (0.156 g,quant.): Major isomer—¹H NMR (500 MHz, CDCl₃) δ 7.53-7.34 (m, 2H),7.27-7.11 (m, 2H), 6.90 (d, J=8.6 Hz, 1H), 6.44 (dd, J=8.6, 2.8 Hz, 1H),5.97 (ddq, J=16.9, 10.1, 6.8 Hz, 1H), 5.29-5.04 (m, 1H), 4.94 (dq,J=16.6, 1.2 Hz, 1H), 4.37-4.16 (m, 2H), 3.88 (s, 2H); ¹⁹F NMR (471 MHz,CDCl₃) δ −110.82 (q, J=7.5 Hz); ESIMS m/z 330 ([M+H]⁺).

5-Amino-2-chloro-N-(2-cyano-4-fluorophenyl)-N-(prop-2-yn-1-yl)benzamide(C101)

A mixture of amide rotamers was isolated as a colorless oil (0.067 g,62%): ¹H NMR (500 MHz, CDCl₃) δ 7.70-7.40 (m, 2H), 7.26-7.15 (m, 1H),7.01-6.64 (m, 2H), 6.46 (dd, J=8.6, 2.8 Hz, 1H), 5.20-4.29 (m, 3H), 3.81(d, J=80.7 Hz, 1H), 2.29 (dt, J=11.8, 2.4 Hz, 1H); ¹⁹F NMR (471 MHz,CDCl₃) δ −110.08 (q, J=7.2 Hz); ESIMS m/z 328 ([M+H]⁺).

(5-Amino-2-chloro-N-(2-cyano-4-fluorophenyl)benzamido)methyl acetate(C102)

A mixture of amide rotamers was isolated as a colorless oil (0.063 g,97%): ¹H NMR (500 MHz, CDCl₃) δ 7.58-7.34 (m, 2H), 7.31-7.14 (m, 2H),6.94-6.62 (m, 2H), 6.49-6.37 (m, 1H), 4.98-4.45 (m, 1H), 4.24 (s, 1H),3.80 (d, J=77.8 Hz, 2H), 1.26 (td, J=7.2, 1.9 Hz, 3H); ¹⁹F NMR (471 MHz,CDCl₃) δ −109.28-−109.86 (m); ESIMS m/z 383 ([M+H]⁺).

2-Chloro-N-(2-cyano-4-fluorophenyl)-N-ethyl-5-nitrobenzamide (C103)

A mixture of amide rotamers was isolated as a white solid (0.110 g,64%): ¹H NMR (500 MHz, CDCl₃) δ 7.58-7.34 (m, 2H), 7.31-7.14 (m, 2H),6.94-6.62 (m, 2H), 6.49-6.37 (m, 1H), 4.98-4.45 (m, 1H), 4.24 (s, 1H),3.80 (m, 2H), 1.26 (td, J=7.2, 1.9 Hz, 3H); ¹⁹F NMR (471 MHz, CDCl₃) δ−108.27 (s), −109.81 (q, J=6.7 Hz); ESIMS m/z 348 ([M+H]⁺).

5-Amino-N-benzyl-2-chloro-N-(2-cyano-4-fluorophenyl)benzamide (C104)

A mixture of amide rotamers was isolated as a white foam (0.206 g, 98%):¹H NMR (500 MHz, CDCl₃) δ 7.38-7.17 (m, 7H), 7.15-6.92 (m, 2H),6.92-6.84 (m, 1H), 6.68 (dd, J=8.8, 2.8 Hz, 1H), 6.41 (dd, J=8.6, 2.8Hz, 1H), 5.76 (d, J=14.5 Hz, 1H), 4.69-4.41 (m, 1H), 3.85 (m, 2H); ¹⁹FNMR (471 MHz, CDCl₃) δ −108.73-−110.02 (m); ESIMS m/z 380 ([M+H]⁺).

tert-ButylN-[3-[(5-amino-2-chloro-benzoyl)-methyl-amino]-2,6-difluoro-phenyl]-N-tert-butoxycarbonyl-carbamate(C105)

A mixture of amide rotamers was isolated as a colorless oil (0.140 g,63%): ¹H NMR (500 MHz, CDCl₃) δ 7.23-7.09 (m, 1H), 7.04-6.86 (m, 1H),6.79-6.64 (m, 1H), 6.50-6.34 (m, 2H), 3.77 (s, 2H), 3.39 (s, 3H), 1.43(d, J=13.3 Hz, 18H); ¹⁹F NMR (471 MHz, CDCl₃) δ −116.85-−118.50 (m),−123.55 (s); ESIMS m/z 534 ([M+Na]⁺).

tert-ButylN-[3-[(5-amino-2-chloro-benzoyl)-methyl-amino]-2,6-difluoro-phenyl]-N-methyl-carbamate(C106)

A mixture of amide rotamers was isolated as a pale yellow foam (0.114 g,92%): ¹H NMR (500 MHz, CDCl₃) δ 7.25-6.86 (m, 2H), 6.85-6.28 (m, 3H),4.50 (dd, J=72.3, 40.3 Hz, 1H), 3.41 (s, 3H), 3.23-2.99 (m, 3H), 1.56(s, 1H), 1.55-1.30 (m, 9H); ¹⁹F NMR (471 MHz, CDCl₃) δ −118.27 (dt,J=10.7, 5.6 Hz), −122.00-−124.47 (m); ESIMS m/z 448 ([M+Na]⁺).

5-Amino-2-chloro-N,N′-dimethyl-N′-phenylbenzohydrazide (C107)

Isolated as a yellow solid (0.203 g, 80%): ¹H NMR (400 MHz, DMSO-d₆) δ7.32-7.22 (m, 2H), 6.99 (d, J=8.4 Hz, 1H), 6.87 (t, J=7.1 Hz, 1H),6.83-6.75 (m, 2H), 6.48 (q, J=2.6 Hz, 2H), 5.24 (s, 2H), 3.04 (s, 3H),2.98 (s, 3H); ESIMS m/z 273 ([M+H]⁺).

tert-Butyl-N-[3-[(5-amino-2-chloro-3-fluorobenzoyl)amino]-2,6-difluorophenyl]-N-tert-butoxycarbonylcarbamate(C108)

Isolated as a light-tan solid (0.864 g, 71%): mp 150-153° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 10.39 (s, 1H), 7.68 (td, J=8.8, 5.8 Hz, 1H), 7.25(td, J=9.2, 1.7 Hz, 1H), 6.59 (ddd, J=7.0, 5.5, 2.5 Hz, 2H), 5.82 (s,2H), 1.40 (s, 18H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −115.54, −123.59,−126.30; HRMS-ESI (m/z) [M+]⁺ calcd for C₂₃H₂₅ClF₃N₃O₅, 515.1435; found,515.1431.

3-Amino-2,6-dichloro-N-(2,2,3,3,3-pentafluoropropyl)benzamide (C109)

Isolated as a tan solid (0.057 g, 82%): mp 116-128° C.; ¹H NMR (400 MHz,CDCl₃) δ 7.10 (d, J=8.7 Hz, 1H), 6.74 (d, J=8.7 Hz, 1H), 6.04 (s, 1H),4.18 (td, J=15.1, 6.5 Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −84.15,−121.50; EIMS m/z 336.

3-Amino-N-ethyl-2,6-difluorobenzamide (C110)

Isolated as a cream-colored solid (0.036 g, 44%): mp 123-126° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 8.56 (t, J=5.6 Hz, 1H), 6.92-6.69 (m, 2H), 5.09 (s,2H), 3.23 (qd, J=7.2, 5.5 Hz, 2H), 1.08 (t, J=7.2 Hz, 3H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −131.96, −131.96, −135.48, −135.49; ESIMS m/z 201([M+H]⁺).

3-Amino-2,6-difluoro-N-(2,2,2-trifluoroethyl)benzamide (C111)

Isolated as a yellow solid (0.106 g, 68%): mp 133-136° C.; ¹H NMR (400MHz, DMSO-d₆) δ 9.30 (t, J=6.3 Hz, 1H), 6.93-6.74 (m, 2H), 5.17 (s, 2H),4.07 (qd, J=9.7, 6.3 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −70.67,−131.95, −131.95, −135.20, −135.21; ESIMS m/z 255 ([M+H]⁺).

3-Amino-2,6-difluoro-N-(2,2,3,3,3-pentafluoropropyl)benzamide (C112)

Isolated as a light-brown solid (0.090 g, 59%): mp 82-85° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 9.31 (t, J=6.3 Hz, 1H), 6.93-6.72 (m, 2H), 5.17 (s,2H), 4.12 (td, J=15.5, 6.4 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −83.42,−120.11, −131.86, −135.12; ESIMS m/z 305 ([M+H]⁺).

3-Amino-2,6-dichloro-N-ethylbenzamide (C113)

Isolated as a peach-colored solid (0.058 g, 68%): mp 179-182° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 8.45 (t, J=5.7 Hz, 1H), 7.10 (d, J=8.7 Hz, 1H),6.77 (d, J=8.8 Hz, 1H), 5.61 (s, 2H), 3.22 (qd, J=7.2, 5.6 Hz, 2H), 1.09(t, J=7.3 Hz, 3H); ESIMS m/z 233 ([M+H]⁺).

3-Amino-2,6-dichloro-N-(2,2,2-trifluoroethyl)benzamide (C114)

Isolated as an orange solid (0.125 g, 77%): mp 178-181° C.; ¹H NMR (400MHz, DMSO-d₆) δ 9.23 (t, J=6.4 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 6.81 (d,J=8.8 Hz, 1H), 5.68 (s, 2H), 4.05 (qd, J=9.7, 6.3 Hz, 2H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −70.05; ESIMS m/z 287 ([M+H]⁺).

3-Amino-2,6-difluoro-N-propylbenzamide (C115)

Isolated as a light-orange oil (0.080 g, 62%): ¹H NMR (400 MHz, DMSO-d₆)δ 8.54 (t, J=5.7 Hz, 1H), 6.90-6.65 (m, 2H), 5.09 (s, 2H), 3.17 (td,J=6.8, 5.7 Hz, 2H), 1.48 (h, J=7.2 Hz, 2H), 0.89 (t, J=7.4 Hz, 3H); ¹⁹FNMR (376 MHz, DMSO-d₆) δ −131.92, −131.93, −135.41, −135.41; ESIMS m/z215 ([M+H]⁺).

3-Amino-2,6-dichloro-N-propylbenzamide (C116)

Isolated as a tan solid (0.089 g, 72%): mp 165-168° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 8.47 (t, J=5.7 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.77 (d,J=8.7 Hz, 1H), 3.16 (td, J=6.8, 5.6 Hz, 2H), 1.50 (h, J=7.2 Hz, 2H),0.91 (t, J=7.4 Hz, 3H); ESIMS m/z 247 ([M+H]⁺).

3-Amino-2,6-difluoro-N-(3,3,3-trifluoropropyl)benzamide (C117)

Isolated as an orange solid (0.104 g, 67%): mp 71-74° C.; ¹H NMR (400MHz, DMSO-d₆) δ 8.81 (t, J=5.7 Hz, 1H), 6.92-6.69 (m, 2H), 5.13 (s, 2H),3.45 (q, J=6.5 Hz, 2H), 2.57-2.43 (m, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−63.90, −131.90, −135.35; ESIMS m/z 269 ([M+H]⁺).

3-Amino-2,6-dichloro-N-(3,3,3-trifluoropropyl)benzamide (C118)

Isolated as a peach-colored solid (0.129 g, 80%): mp 144-147° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 8.77 (t, J=5.7 Hz, 1H), 7.11 (d, J=8.7 Hz, 1H),6.79 (d, J=8.8 Hz, 1H), 5.65 (s, 2H), 3.43 (td, J=6.9, 5.7 Hz, 2H),2.58-2.44 (m, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −64.00; ESIMS m/z 301([M+H]⁺).

3-Amino-2,6-dichloro-N-(2-fluoroethyl)benzamide (C119)

Isolated as a peach-colored solid (0.092 g, 74%): mp 170-172° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 8.78 (t, J=5.6 Hz, 1H), 7.11 (d, J=8.7 Hz, 1H),6.78 (d, J=8.8 Hz, 1H), 5.63 (s, 2H), 4.50 (dt, J=47.4, 5.1 Hz, 2H),3.51 (dq, J=26.6, 5.3 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ 16.09; ESIMSm/z 251 ([M+H]⁺).

3-Amino-2,6-dichloro-N-(3-chloropropyl)benzamide (C120)

Isolated as a peach solid (0.128 g, 84%): mp 124-127° C.; ¹H NMR (400MHz, DMSO-d₆) δ 8.59 (t, J=5.7 Hz, 1H), 7.11 (d, J=8.7 Hz, 1H), 6.78 (d,J=8.8 Hz, 1H), 5.64 (s, 2H), 3.71 (t, J=6.6 Hz, 2H), 3.33 (d, J=5.8 Hz,5H), 1.95 (p, J=6.7 Hz, 2H); ESIMS m/z 281 ([M+H]⁺).

3-Amino-2,6-difluoro-N-(2-fluoroethyl)benzamide (C121)

Isolated as a purple solid (0.079 g, 74%): mp 97-99° C.; ¹H NMR (400MHz, DMSO-d₆) δ 8.83 (t, J=5.6 Hz, 1H), 6.89-6.71 (m, 2H), 5.11 (s, 2H),4.49 (dt, J=47.5, 5.0 Hz, 2H), 3.52 (dq, J=27.0, 5.2 Hz, 2H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ 15.42, −131.81, −131.82, −135.24, −135.25; ESIMSm/z 219 ([M+H]⁺).

3-Amino-N-(3-chloropropyl)-2,6-difluorobenzamide (C122)

Isolated as an amber oil (0.083 g, 73%): ¹H NMR (400 MHz, DMSO-d₆) δ8.67 (t, J=5.7 Hz, 1H), 6.93-6.66 (m, 2H), 5.12 (s, 2H), 3.68 (t, J=6.6Hz, 2H), 3.34 (q, J=6.4 Hz, 2H), 1.93 (p, J=6.6 Hz, 2H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −132.00, −132.00, −135.48, −135.48; ESIMS m/z 249([M+H]⁺).

3-Amino-N-(2,4-difluorophenyl)-2,6-difluorobenzamide (C123)

Isolated as a peach-colored solid (0.077 g, 46%): mp 147-150° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 10.51 (s, 1H), 7.75 (td, J=8.9, 6.1 Hz, 1H), 7.37(ddd, J=11.4, 9.2, 2.8 Hz, 1H), 7.12 (tt, J=8.7, 1.9 Hz, 1H), 6.95-6.77(m, 2H), 5.20 (s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −113.26, −113.28,−117.37, −117.39, −131.64, −131.65, −134.94, −134.95; ESIMS m/z 285([M+H]⁺).

3-Amino-2,6-difluoro-N-(4-fluorophenyl)benzamide (C124)

Isolated as a light-orange solid (0.114 g, 77%): mp 164-167° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 10.74 (s, 1H), 7.82-7.62 (m, 2H), 7.20 (t, J=8.9Hz, 2H), 7.04-6.68 (m, 2H), 5.22 (s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−118.34, −118.36, −131.90, −131.90, −135.32, −135.33; ESIMS m/z 267([M+H]⁺).

N-(4-Acetamidophenyl)-3-amino-2,6-difluorobenzamide (C125)

Isolated as a white solid (0.017 g, 54%): mp 210-213° C.; ¹H NMR (400MHz, DMSO-d₆) δ 10.59 (s, 1H), 9.92 (s, 1H), 7.60 (d, J=9.0 Hz, 2H),7.54 (d, J=9.0 Hz, 2H), 6.94-6.77 (m, 2H), 5.19 (s, 2H), 2.03 (s, 3H);¹⁹F NMR (376 MHz, DMSO-d₆) δ −131.84, −131.85, −135.29, −135.30; ESIMSm/z 306 ([M+H]⁺).

N-(4-Acetamidophenyl)-3-amino-2,6-dichlorobenzamide (C126)

Isolated as a gray solid (0.029 g, 25%): mp 215-278° C.; ¹H NMR (400MHz, DMSO-d₆) δ 10.50 (s, 1H), 9.91 (s, 1H), 7.62-7.56 (m, 2H),7.56-7.50 (m, 2H), 7.17 (d, J=8.8 Hz, 1H), 6.84 (d, J=8.8 Hz, 1H), 5.70(s, 2H), 2.02 (s, 3H); ESIMS m/z 338 ([M+H]⁺).

3-Amino-2,6-dichloro-N-(4-fluorophenyl)benzamide (C127)

Isolated as a white solid (0.093 g, 81%): mp 204-207° C.; ¹H NMR (400MHz, DMSO-d₆) δ 10.65 (s, 1H), 7.75-7.66 (m, 2H), 7.24-7.14 (m, 3H),6.85 (d, J=8.8 Hz, 1H), 5.73 (s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−118.56; ESIMS m/z 299 ([M+H]⁺).

3-Amino-2,6-dichloro-N-phenylbenzamide (C128)

Isolated as a white solid (0.129 g, 91%): mp 172-175; ¹H NMR (400 MHz,DMSO-d₆) δ 10.58 (s, 1H), 7.73-7.63 (m, 2H), 7.41-7.27 (m, 2H), 7.18 (d,J=8.8 Hz, 1H), 7.14-7.06 (m, 1H), 6.85 (d, J=8.8 Hz, 1H), 5.72 (s, 2H),ESIMS m/z 281 ([M+H]⁺).

3-Amino-2,6-dichloro-N-(2,4-difluorophenyl)benzamide (C129)

Isolated as a white solid (0.127 g, 87%): mp 187-189° C.; ¹H NMR (400MHz, DMSO-d₆) δ 10.47 (s, 1H), 7.76 (td, J=8.9, 6.2 Hz, 1H), 7.35 (ddd,J=10.7, 9.1, 2.9 Hz, 1H), 7.23-7.08 (m, 2H), 6.84 (d, J=8.8 Hz, 1H),5.71 (s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −113.48, −113.50, −117.40,−117.41; ESIMS m/z 317 ([M+H]⁺).

3-Amino-N-(4-aminophenyl)-2,6-dichloro-N-methylbenzamide (C130)

Isolated as a waxy gray solid (0.052 g, 80%): ¹H NMR (400 MHz, DMSO-d₆)δ 7.03-6.89 (m, 3H), 6.58 (d, J=8.7 Hz, 1H), 6.38-6.31 (m, 2H), 5.47 (s,2H), 5.10 (s, 2H), 3.24 (s, 3H); ESIMS m/z 310 ([M+H]⁺).

tert-Butyl-N-[3-[(3-amino-2,6-dichlorobenzoyl)amino]-2,6-difluorophenyl]-N-tert-butoxycarbonylcarbamate(C131)

Isolated as a waxy white solid (0.166 g, 61%): mp 84-89° C.; ¹H NMR (400MHz, DMSO-d₆) δ 10.58 (s, 1H), 7.76 (td, J=8.8, 5.8 Hz, 1H), 7.26 (td,J=9.2, 1.7 Hz, 1H), 7.18 (d, J=8.7 Hz, 1H), 6.85 (d, J=8.8 Hz, 1H), 5.73(s, 2H), 1.40 (s, 18H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −123.71, −126.64;ESIMS m/z 530 ([M−H]⁻).

3-Amino-2,6-difluoro-N-phenylbenzamide (C132)

Isolated as a tan solid (0.109 g, 85%): mp 173-176° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 10.67 (s, 1H), 7.75-7.64 (m, 2H), 7.41-7.30 (m, 2H),7.19-7.07 (m, 1H), 6.98-6.77 (m, 2H), 5.21 (s, 2H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −131.91, −131.92, −135.34, −135.35; ESIMS m/z 249 ([M+H]⁺).

tert-Butyl-N-[3-[(3-amino-2,6-difluorobenzoyl)amino]-2,6-difluorophenyl]-N-tert-butoxycarbonylcarbamate(C133)

Isolated as an orange solid (0.086 g, 61%): mp 148-151° C.; ¹H NMR (400MHz, DMSO-d₆) δ 10.62 (s, 1H), 7.75 (td, J=8.8, 5.8 Hz, 1H), 7.26 (td,J=9.3, 1.7 Hz, 1H), 6.99-6.78 (m, 2H), 5.22 (s, 2H), 1.40 (s, 18H); ¹⁹FNMR (376 MHz, DMSO-d₆) δ −123.58, −126.68, −131.69, −131.70, −134.99,−135.00; ESIMS m/z 498 ([M−H]⁻).

Example 58 Preparation of tert-Butyl(4-(5-amino-2-chlorobenzamido)-3-methylphenyl)carbamate (C134)

To a solution of tert-butyl(4-(2-chloro-5-nitrobenzamido)-3-methylphenyl)carbamate (C153) (2.2 g,5.42 mmol) in ethyl acetate (54 mL) under N₂ was added Pd/C (0.95 g,0.445 mmol). The reaction mixture was placed under approx. oneatmosphere of hydrogen (balloon) and stirred overnight at roomtemperature. The reaction mixture was filtered through a plug of Celite®and concentrated under reduced pressure to afford the title compound asa brown foam (2.09 g, 92%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.68 (s, 1H),9.28 (s, 1H), 7.35 (d, J=2.2 Hz, 1H), 7.26 (dd, J=8.6, 2.4 Hz, 1H), 7.18(d, J=8.6 Hz, 1H), 7.12 (d, J=8.6 Hz, 1H), 6.75 (d, J=2.7 Hz, 1H), 6.64(dd, J=8.6, 2.7 Hz, 1H), 5.64 (s, 2H), 2.21 (s, 3H), 1.48 (s, 9H); ¹³CNMR (101 MHz, DMSO-d₆) δ 165.69, 152.77, 147.30, 137.32, 137.27, 133.57,130.14, 129.79, 126.41, 119.77, 115.93, 115.55, 113.84, 78.91, 54.86,28.13, 18.21; ESIMS m/z 374 ([M−H]⁻).

The following compounds were prepared in like manner to the procedureoutlined in Example 58:

tert-Butyl-N-((tert-butoxy)carbonyl)-N-(3-(5-amino-2-chlorobenzamido)-2,6-difluorophenyl)carbamate(C135)

Isolated as a white solid (2.89 g, 59%): ¹H NMR (400 MHz, DMSO-d₆) δ10.28 (s, 1H), 7.67 (td, J=8.8, 5.8 Hz, 1H), 7.24 (td, J=9.3, 1.7 Hz,1H), 7.13 (d, J=8.6 Hz, 1H), 6.73 (d, J=2.7 Hz, 1H), 6.65 (dd, J=8.6,2.8 Hz, 1H), 5.48 (s, 2H), 1.40 (s, 18H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−123.86, −126.24; ESIMS m/z 496 ([M−H]⁻).

5-Amino-2-chloro-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(C136)

Isolated as a brown foam (0.485 g, 97%): ESIMS m/z 376 ([M+H]+). ¹H NMR(400 MHz, DMSO-d₆) δ 10.77 (s, 1H), 10.28 (s, 1H), 7.73-7.54 (m, 1H),7.31-7.18 (m, 1H), 7.13 (d, J=8.6 Hz, 1H), 6.73 (d, J=2.8 Hz, 1H),6.70-6.27 (m, 2H), 5.49 (s, 2H). ¹⁹F NMR (376 MHz, DMSO-d₆) δ −120.94(d, J=2.6 Hz), −124.00 (d, J=2.7 Hz), −125.80.

Example 59 Preparation oftert-butyl-N-((tert-butoxyl)carbonyl)-N-(5-(5-amino-2-chlorobenzamido)-2,4-difluorophenyl)carbamate(C137)

To a vial containingtert-butyl-N-((tert-butoxy)carbonyl)-N-(5-amino-2,4-difluorophenyl)carbamate(C183) (0.4 g, 1.16 mmol) were added 2-chloro-5-nitrobenzoic acid (0.23g, 1.16 mmol), 4-dimethylaminopyridine (0.15 g, 1.28 mmol),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.33 g, 1.74 mmol), anddichloromethane (6 mL). The reaction mixture was stirred at roomtemperature for 18 h then was directly loaded onto a prepacked Celite®cartridge and flushed through a silica gel column with ethylacetate/hexanes. The resulting yellow foam was dissolved in ethylacetate (2 mL) and 10% palladium on carbon (10 mg, 0.009 mmol) wasadded. The slurry was stirred under an atmosphere of hydrogen gas(balloon) for 7 hours. The slurry was filtered through a pad of Celite®with ethyl acetate and concentrated. Purification by flash columnchromatography gave the title compound as a white foam (0.1479 g, 25%):¹H NMR (400 MHz, DMSO-d₆) δ 10.27 (s, 1H), 7.67 (t, J=8.1 Hz, 1H), 7.50(t, J=10.1 Hz, 1H), 7.12 (d, J=8.6 Hz, 1H), 6.73 (d, J=2.7 Hz, 1H), 6.65(dd, J=8.6, 2.7 Hz, 1H), 5.48 (s, 2H), 1.40 (s, 18H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −117.30 (d, J=6.4 Hz), −122.18 (d, J=6.4 Hz); ESIMS m/z 495.6[(M−H]⁻).

Example 60 Preparation of2-cyano-N-(2,4-difluorophenyl)-N-methyl-5-nitrobenzamide (C138)

To a solution of2-bromo-N-(2,4-difluorophenyl)-N-methyl-5-nitrobenzamide (0.120 g, 0.323mmol) (C149) in N,N-dimethylformamide (1.6 mL) was added copper(I)cyanide (0.145 g, 1.62 mmol). The reaction mixture was degassed undervacuum, backfilled with nitrogen, capped in a 2-mL microwave vial, andheated at 160° C. for 20 minutes in a Biotage Initiator® microwavereactor with external IR-sensor temperature monitoring from the side ofthe vessel. The reaction mixture was diluted with ethyl acetate whilestirring vigorously and then filtered through Celite® washing with ethylacetate. The filtrate was washed with brine. The organic phase was driedover magnesium sulfate, filtered, and concentrated. Purification byflash column chromatography using 0-25% ethyl acetate/hexanes as eluentprovided the title compound as a mixture of amide rotamers as a beigesolid (0.051 g, 47%): ¹H NMR (500 MHz, CDCl₃) δ 8.20 (d, J=8.1 Hz, 2H),7.81-7.72 (m, 1H), 7.39 (td, J=8.8, 5.7 Hz, 1H), 6.86 (dddd, J=8.9, 7.5,2.8, 1.5 Hz, 1H), 6.76 (ddd, J=10.6, 8.3, 2.8 Hz, 1H), 3.50 (s, 3H); ¹⁹FNMR (471 MHz, CDCl₃) δ −106.15 (h, J=8.1 Hz), −115.12 (q, J=8.9 Hz);ESIMS m/z 318 ([M+H]⁺).

Example 61 Preparation ofN-allyl-2-chloro-N-(2-cyano-4-fluorophenyl)-5-nitrobenzamide (C139)

To a solution of 2-chloro-N-(2-cyano-4-fluorophenyl)-5-nitrobenzamide(C152) (0.200 g, 0.626 mmol) in tetrahydrofuran (6.3 mL) cooled in anice bath was added sodium hydride (60% oil immersion, 0.030 g, 0.75mmol). The slurry was stirred for 30 minutes, and allyl bromide (0.081mL, 0.94 mmol) was added. The reaction mixture was stirred for 18 hours.The reaction was quenched by the slow addition of water (10 mL) anddiluted with ethyl acetate (10 mL). The organic layer was dried overmagnesium sulfate, filtered, and concentrated. Purification by flashcolumn chromatography using 0-25% ethyl acetate/hexanes as eluentprovided the title compound as a mixture of amide rotamers as anoff-white solid (0.162 g, 68%): Major isomer—¹H NMR (500 MHz, CDCl₃) δ8.31 (d, J=2.7 Hz, 1H), 8.05 (dd, J=8.8, 2.7 Hz, 1H), 7.42 (d, J=8.8 Hz,1H), 7.40 (s, 1H), 7.30 (dd, J=7.4, 2.9 Hz, 1H), 7.20 (ddd, J=8.9, 7.5,3.0 Hz, 1H), 5.99 (ddt, J=17.0, 10.1, 6.7 Hz, 1H), 5.30-5.17 (m, 2H),4.89 (dd, J=14.6, 6.0 Hz, 1H), 4.29 (dd, J=14.6, 7.5 Hz, 1H); ¹⁹F NMR(471 MHz, CDCl₃) δ −108.13 (q, J=6.9 Hz); ESIMS m/z 360 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 61:

2-Chloro-N-(2-cyano-4-fluorophenyl)-5-nitro-N-(prop-2-yn-1-yl)benzamide(C140)

A mixture of amide rotamers was isolated as a white foam (0.128 g,quant.): Major isomer—¹H NMR (500 MHz, CDCl₃) δ 8.30 (d, J=2.6 Hz, 1H),8.07 (dd, J=8.8, 2.6 Hz, 1H), 7.54 (dt, J=6.7, 3.4 Hz, 1H), 7.43 (d,J=8.8 Hz, 1H), 7.33 (dd, J=7.3, 2.9 Hz, 1H), 7.23 (ddd, J=8.9, 7.5, 3.0Hz, 1H), 5.21 (dd, J=17.4, 2.5 Hz, 1H), 4.41 (m, 1H), 2.34 (t, J=2.5 Hz,1H); ¹⁹F NMR (471 MHz, CDCl₃) δ −107.37 (q, J=6.8 Hz); ESIMS m/z 358([M+H]⁺).

(2-Chloro-N-(2-cyano-4-fluorophenyl)-5-nitrobenzamido)methyl acetate(C141)

A mixture of amide rotamers was isolated as a yellow oil (0.067 g, 52%):¹H NMR (500 MHz, CDCl₃) δ 8.50-8.34 (m, 1H), 8.35-8.04 (m, 1H),7.73-7.39 (m, 3H), 7.34-7.19 (m, 1H), 5.99-5.80 (m, 1H), 5.56-5.28 (m,1H), 2.14 (d, J=4.0 Hz, 3H); ¹⁹F NMR (471 MHz, CDCl₃) δ −108.78 (q,J=7.0 Hz); ESIMS m/z 392 ([M+H]⁺).

2-Chloro-N-(2-cyano-4-fluorophenyl)-N-ethyl-5-nitrobenzamide (C142)

A mixture of amide rotamers was isolated as a white solid (0.110 g,64%): Major isomer—¹H NMR (500 MHz, CDCl₃) δ 8.32-8.28 (m, 1H), 8.04(dd, J=8.8, 2.7 Hz, 1H), 7.40 (dd, J=8.9, 5.2 Hz, 2H), 7.32 (dd, J=7.4,2.9 Hz, 1H), 7.22 (ddd, J=8.9, 7.4, 2.9 Hz, 1H), 4.27 (dq, J=14.2, 7.2Hz, 1H), 3.84 (dq, J=14.1, 7.1 Hz, 1H), 1.31 (t, J=7.2 Hz, 3H); ¹⁹F NMR(471 MHz, CDCl₃) δ −108.27 (s); ESIMS m/z 348 ([M+H]⁺).

N-Benzyl-2-chloro-N-(2-cyano-4-fluorophenyl)-5-nitrobenzamide (C143)

A mixture of amide rotamers was isolated as a white foam (0.216 g, 80%):¹H NMR (500 MHz, CDCl₃) δ 8.32-8.27 (m, 1H), 8.03 (dd, J=8.8, 2.6 Hz,1H), 7.40 (d, J=8.8 Hz, 1H), 7.33-7.24 (m, 6H), 7.02-6.92 (m, 2H), 5.77(m, 1H), 4.60 (m, 1H); ¹⁹F NMR (471 MHz, CDCl₃) δ −107.79-−108.26 (m);ESIMS m/z 410 ([M+H]⁺).

tert-ButylN-tert-butoxycarbonyl-N-[3-[(2-chloro-5-nitro-benzoyl)-methyl-amino]-2,6-difluoro-phenyl]carbamate(C144)

A mixture of amide rotamers was isolated as a pale yellow oil (0.179 g,55%): ¹H NMR (500 MHz, CDCl₃) δ 8.15 (dd, J=2.6, 1.5 Hz, 1H), 8.03 (dd,J=8.8, 2.7 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.29-7.23 (m, 1H), 6.81 (td,J=8.8, 1.9 Hz, 1H), 3.45 (s, 3H), 1.41 (dd, J=39.8, 7.5 Hz, 18H); ¹⁹FNMR (471 MHz, CDCl₃) δ −115.52 (s), −120.91-−123.25 (m); ESIMS m/z 541([M+H]⁺).

tert-ButylN-[3-[allyl-(2-chloro-5-nitro-benzoyl)amino]-2,6-difluoro-phenyl]-N-tert-butoxycarbonyl-carbamate(C145)

A mixture of amide rotamers was isolated as a colorless oil (0.068 g,38%): ¹H NMR (500 MHz, CDCl₃) δ 8.16 (t, J=2.2 Hz, 1H), 8.03 (dd, J=8.8,2.7 Hz, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.31-7.22 (m, 1H), 6.81 (td, J=8.8,1.8 Hz, 1H), 5.95 (ddt, J=16.9, 10.2, 6.6 Hz, 1H), 5.26-5.16 (m, 2H),4.61 (dd, J=14.9, 6.3 Hz, 1H), 4.34 (dd, J=14.7, 6.9 Hz, 1H), 1.46-1.32(m, 18H); ¹⁹F NMR (471 MHz, CDCl₃) δ −114.18-−116.23 (m), −121.37 (s);ESIMS m/z 590 ([M+Na]⁺).

tert-ButylN-tert-butoxycarbonyl-N-[3-[(2-chloro-5-nitro-benzoyl)-prop-2-ynyl-amino]-2,6-difluoro-phenyl]carbamate(C146)

A mixture of amide rotamers was isolated as a beige sticky solid (0.144g, 85%): ¹H NMR (500 MHz, CDCl₃) δ 8.17 (t, J=2.2 Hz, 1H), 8.04 (dd,J=8.8, 2.7 Hz, 1H), 7.47-7.40 (m, 1H), 7.37 (d, J=8.8 Hz, 1H), 6.84 (td,J=8.8, 1.8 Hz, 1H), 4.99 (d, J=17.4 Hz, 1H), 4.43-4.31 (m, 1H), 2.29 (t,J=2.5 Hz, 1H), 1.40 (dd, J=31.4, 3.8 Hz, 18H); ¹⁹F NMR (471 MHz, CDCl₃)δ −114.79 (s), −121.53 (s); ESIMS m/z 588 ([M+Na]⁺).

tert-Butyl(3-(2-chloro-N-methyl-5-nitrobenzamido)-2,6-difluorophenyl)(methyl)carbamate(C147)

A mixture of amide rotamers was isolated as a colorless oil (0.071 g,26%): ¹H NMR (500 MHz, CDCl₃) δ 8.16 (d, J=51.3 Hz, 1H), 8.03 (ddd,J=9.6, 6.8, 2.6 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.21-6.98 (m, 1H),6.86-6.57 (m, 1H), 3.65-3.43 (m, 3H), 3.22-2.92 (m, 3H), 1.40 (m, 9H);¹⁹F NMR (471 MHz, CDCl₃) δ −115.40 (s), −122.10 (s); ESIMS m/z 455([M+H]⁺).

Example 62 Preparation ofN-(2,6-difluoro-3-nitrophenyl)-2,2-difluoro-N-methylacetamide (C148)

To a solution of N-(2,6-difluoro-3-nitrophenyl)-2,2-difluoroacetamide(C193) (0.400 g, 1.59 mmol) in dry N,N-dimethylformamide (12 mL) cooledin an ice bath was added sodium hydride (60% oil dispersion, 0.076 g,1.90 mmol). The slurry was stirred for 5 minutes in the ice bath. Thebath was removed and the reaction was stirred an additional 40 minutes.Iodomethane (0.099 mL, 1.59 mmol) was added. The reaction mixture wasstirred at room temperature overnight. The reaction was quenched withwater (15 mL) and diluted with ethyl acetate (40 mL). The phases wereseparated, and the organic layer was washed with 1:1 brine/water (4×20mL). The organic layer was poured through a phase separator to dry andthen concentrated under reduced pressure to afford the title compound asa yellow oil (0.30 g, 71%): ¹H NMR (400 MHz, DMSO-d₆) δ rotamers 8.45(ddd, J=9.5, 8.5, 5.7 Hz, 0.65H), 8.36 (ddd, J=9.5, 8.4, 5.5 Hz, 0.35H),7.69-7.52 (m, 1H), 7.05 (t, J=52.1 Hz, 0.35H), 6.43 (t, J=51.6 Hz,0.65H), 3.43 (d, J=1.2 Hz, 1H), 3.25 (s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆)δ 0 rotamers −106.63 (d, J=10.3 Hz), −106.82-−107.10 (m),−120.60-−120.78 (m), −120.98 (d, J=10.4 Hz), −124.26-−124.99 (m),−124.80-−125.41 (m), −126.78 (d, J=3.4 Hz); EIMS m/z 266.

Example 63 Preparation of2-bromo-N-(2,4-difluorophenyl)-N-methyl-5-nitrobenzamide (C149)

2-Bromo-5-nitrobenzoic acid (0.500 g, 2.03 mmol) and4-dimethylaminopyridine (0.273 g, 2.24 mmol) were sequentially added toa stirred mixture of 2,4-difluoro-N-methylaniline (0.349 mL, 2.44 mmol)and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.584g, 3.05 mmol) in dichloromethane (13.5 mL) at room temperature. Thereaction was stirred at room temperature for 20 hours. The reactionmixture was diluted with dichloromethane and washed with saturatedaqueous sodium bicarbonate followed by hydrochloric acid (1 N). Theorganic phase was dried over magnesium sulfate, filtered, andconcentrated. Purification by flash column chromatography using 0-25%ethyl acetate/hexanes as eluent provided the title compound as a beigesolid (0.149 g, 19%): ¹HNMR (500 MHz, CDCl₃) δ 8.29 (d, J=2.7 Hz, 0H),8.21-8.14 (m, 0H), 8.07 (dd, J=2.7, 1.4 Hz, 1H), 7.93 (dd, J=8.8, 2.7Hz, 1H), 7.86 (dd, J=8.7, 6.2 Hz, 0H), 7.61 (d, J=8.8 Hz, 1H), 7.47-7.39(m, 0H), 7.30 (dt, J=9.0, 4.5 Hz, 1H), 7.04-6.97 (m, 0H), 6.83-6.72 (m,2H), 3.45 (s, 4H), 3.19 (s, 1H); 19F NMR (471 MHz, CDCl₃) δ −106.76 ,−108.81 (dt, J=14.9, 7.9 Hz), −114.38 , −115.36 (q, J=8.6 Hz); ESIMS m/z373 ([M+H]⁺).

Example 64 Preparation of 2-chloro-N-(4-fluorophenyl)-5-nitrobenzamide(C150)

2-Chloro-5-nitrobenzoic acid (0.250 g, 1.24 mmol) and4-dimethylaminopyridine (0.197 g, 1.61 mmol) were sequentially added toa stirred mixture of 4-fluoroaniline (0.141 mL, 1.49 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.357 g,1.86 mmol) in 1,2-dichloroethane (12.4 mL) at room temperature. Thereaction was stirred at room temperature for 20 hours. The reactionmixture was diluted with dichloromethane and washed with saturatedaqueous sodium bicarbonate followed by hydrochloric acid (1 N) toprovide the title compound as a light brown solid (0.188 g, 49%): ¹H NMR(400 MHz, CDCl₃) δ 8.59 (d, J=2.7 Hz, 1H), 8.26 (dd, J=8.8, 2.8 Hz, 1H),7.90 (s, 1H), 7.66 (d, J=8.8 Hz, 1H), 7.64-7.57 (m, 2H), 7.15-7.05 (m,2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −116.03; ESIMS m/z 295 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 64:

2-Chloro-N-(2,4-difluorophenyl)-5-nitrobenzamide (C151)

Isolated as a light purple solid (1.48 g, 64%): ¹H NMR (400 MHz, CDCl₃)δ 8.68 (d, J=2.7 Hz, 1H), 8.40 (td, J=9.1, 6.7 Hz, 1H), 8.30 (dd, J=8.8,2.7 Hz, 1H), 8.09 (s, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.04-6.89 (m, 2H);¹⁹F NMR (376 MHz, CDCl₃) δ −113.04 (d, J=5.0 Hz), −125.45 (d, J=5.1 Hz);ESIMS m/z 313 ([M+H]⁺).

2-Chloro-N-(2-cyano-4-fluorophenyl)-5-nitrobenzamide (C152)

Isolated as a white solid (0.439 g, 55%): ¹H NMR (400 MHz, DMSO-d₆) δ11.06 (s, 1H), 8.52 (d, J=2.8 Hz, 1H), 8.38 (dd, J=8.8, 2.8 Hz, 1H),8.02-7.86 (m, 2H), 7.83-7.61 (m, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−113.90; ESIMS m/z 320 ([M+H]⁺).

tert-Butyl (4-(2-chloro-5-nitrobenzamido)-3-methylphenyl)carbamate(C153)

Isolated as a yellow solid (2.19 g, 67%): mp 195-200° C.; ¹H NMR (300MHz, DMSO-d₆) δ 10.06 (s, 1H), 9.34 (s, 1H), 8.45 (d, J=2.7 Hz, 1H),8.33 (dd, J=8.8, 2.8 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.43-7.24 (m, 3H),2.24 (s, 3H), 1.48 (s, 9H); ESIMS m/z 404 ([M−H]⁻).

tert-Butyl-N-((tert-butoxy)carbonyl)-N-(3-(2-chloro-5-nitrobenzamido)-2,4-difluorophenyl)carbamate(C154)

Isolated as a yellow oil (5.2 g, 66%): ¹H NMR (400 MHz, DMSO-d₆) δ 10.69(s, 1H), 8.51 (d, J=2.7 Hz, 1H), 8.35 (dd, J=8.8, 2.8 Hz, 1H), 7.97-7.79(m, 2H), 7.30 (td, J=9.3, 1.7 Hz, 1H), 1.41 (s, 18H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −123.43, −127.02 (d, J=2.0 Hz); ESIMS m/z 526 ([M−H]⁻).

Example 65 Preparation oftert-Butyl-N-tert-butoxycarbonyl-N-[3-[(2-chloro-3-fluoro-5-nitrobenzoyl)amino]-2,6-difluorophenyl]carbamate(C155)

To a solution of 2-chloro-3-fluoro-5-nitrobenzoic acid (C206) (1.81 g,8.25 mmol) and tert-butylN-(5-amino-2,6-difluorophenyl)-N-tert-butoxycarbonyl carbamate (C182)(2.84 g, 8.25 mmol) in ethyl acetate (41 mL) were added pyridine (1.96g, 24.7 mmol) followed by a 50% solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (9.82mL, 16.5 mmol) in ethyl acetate, and the resulting gold solution waswarmed to 48° C. and stirred for 12 hours. The reaction mixture wasconcentrated under reduced pressure to give a viscous, gold oil. The oilwas dissolved in minimal dichloromethane (˜8 mL) and adsorbed toCelite®. The adsorbed material was purified by automated flashchromatography using a gradient of 0-40% ethyl acetate in hexanes togive the title compound as a white solid (2.095 g, 83%): mp 167-169° C.;¹H NMR (400 MHz, DMSO-d₆) δ 10.76 (s, 1H), 8.52 (dd, J=8.8, 2.6 Hz, 1H),8.43 (dd, J=2.6, 1.4 Hz, 1H), 7.89 (td, J=8.9, 5.8 Hz, 1H), 7.31 (td,J=9.3, 1.8 Hz, 1H), 1.41 (s, 18H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.64,−123.26, −127.07, −127.08; HRMS-ESI (m/z) [M+]⁺ calcd forC₂₃H₂₃ClF₃N₃O₇, 545.1177; found, 545.1172.

Example 66 Preparation of2,6-dichloro-N-(2,4-difluorophenyl)-3-nitrobenzamide (C156)

Step 1: To a suspension of 2,6-dichloro-3-nitrobenzoic acid (0.15 g,0.64 mmol) in 1,2-dichloroethane (10 mL) were added two drops ofN,N-dimethylformamide followed by the dropwise addition of oxalyldichloride (0.40 g, 0.27 mL, 3.2 mmol), and the resulting light-yellowsolution was stirred at room temperature for 16 hours. The solvent andexcess oxalyl dichloride were evaporated under reduced pressure, and theresulting gold oil was dissolved in 1,2-dichloroethane (10 mL) andconcentrated (repeated 2×) to give the intermediate acid chloride as agold oil which was used without purification.

Step 2: To a solution of 2,4-difluoroaniline (0.082 g, 0.64 mmol) andN-ethyl-N-isopropylpropan-2-amine (0.17 g, 1.34 mmol) in1,2-dichloroethane(1 mL) was added a solution of the freshly preparedacid chloride, 2,6-dichloro-3-nitrobenzoyl chloride (0.162 g, 0.64 mmol)in 1,2-dichloroethane (1 mL) dropwise at 0° C. The resultinglight-orange solution was warmed to 50° C. and stirred for 8 hours. Thereaction mixture was adsorbed to Celite® and purified by automated flashchromatography using a gradient of 0-60% ethyl acetate in hexanes aseluent to give the title compound as a tan solid (0.171 g, 75%): mp199-202° C.; ¹H NMR (500 MHz, DMSO-d₆) δ 10.83 (s, 1H), 8.21 (d, J=8.8Hz, 1H), 7.94 (td, J=8.9, 6.1 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.41(ddd, J=10.9, 9.0, 2.9 Hz, 1H), 7.17 (dddd, J=9.5, 8.4, 2.9, 1.4 Hz,1H); ¹⁹F NMR (471 MHz, DMSO-d₆) δ −112.94, −112.95, −112.96, −112.96,−112.97, −112.97, −112.98, −112.99, −113.00, −118.60, −118.62, −118.62,−118.64, −118.64, −118.66; ESIMS m/z 347 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 66:

N-(4-Acetamidophenyl)-2,6-dichloro-3-nitrobenzamide (C157)

Isolated as a light-yellow solid (0.153 g, 63%): mp 268-270° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 10.82 (s, 1H), 9.97 (s, 1H), 8.20 (d, J=8.8 Hz,1H), 7.89 (d, J=8.8 Hz, 1H), 7.58 (s, 4H), 2.04 (s, 3H); IR (thin film)3640, 3250, 3054, 1656, 1527, 1310, 827, 706 cm⁻¹; ESIMS m/z366([M−2H]⁻).

2,6-Dichloro-N-(4-fluorophenyl)-3-nitrobenzamide (C158)

Isolated as a light-orange solid (0.148 g, 70%): mp 211-214° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 10.98 (s, 1H), 8.22 (d, J=8.8 Hz, 1H), 7.90 (d,J=8.8 Hz, 1H), 7.77-7.63 (m, 2H), 7.34-7.11 (m, 2H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −117.60; ESIMS m/z 329 ([M+H]⁺).

2,6-Dichloro-3-nitro-N-phenylbenzamide (C159)

Isolated as a light-orange solid (0.173 g, 86%): mp 180-183° C.; ¹H NMR(500 MHz, DMSO-d₆) δ 10.90 (s, 1H), 8.22 (d, J=8.7 Hz, 1H), 7.90 (d,J=8.7 Hz, 1H), 7.70-7.64 (m, 2H), 7.42-7.34 (m, 2H), 7.22-7.08 (m, 1H);ESIMS m/z 311 ([M+H]⁺).

N-(4-Aminophenyl)-2,6-dichloro-N-methyl-3-nitrobenzamide (C160)

Isolated as a green solid (0.085 g, 36%): mp 176-180° C.; ¹H NMR (500MHz, DMSO-d₆) δ 7.93 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.7 Hz, 1H),7.02-6.97 (m, 2H), 6.41-6.35 (m, 2H), 5.23 (s, 2H), 3.30 (s, 3H); ESIMSm/z 340 ([M+H]⁺).

tert-Butyl-N-tert-butoxycarbonyl-N-[3-[(2,6-dichloro-3-nitrobenzoyl)amino]-2,6-difluorophenyl]carbamate(C161)

Isolated as a light-orange solid (0.302 g, 78%): mp 164-167° C.; ¹H NMR(500 MHz, DMSO-d₆) δ 10.93 (s, 1H), 8.23 (d, J=8.8 Hz, 1H), 7.97-7.84(m, 2H), 7.31 (td, J=9.3, 1.7 Hz, 1H), 1.40 (s, 18H); ¹⁹F NMR (471 MHz,DMSO-d₆) δ −123.11, −123.12, −123.14, −127.55, −127.57; ESIMS m/z 560([M−H]⁻).

2,6-Difluoro-3-nitro-N-phenylbenzamide (C162)

Isolated as a yellow solid (0.161 g, 90%): mp 161-163° C.; ¹H NMR (500MHz, DMSO-d₆) δ 10.98 (s, 1H), 8.42 (td, J=9.0, 5.6 Hz, 1H), 7.71-7.63(m, 2H), 7.56 (ddd, J=9.4, 7.9, 1.5 Hz, 1H), 7.44-7.35 (m, 2H),7.24-7.14 (m, 1H); ¹⁹F NMR (471 MHz, DMSO-d₆) δ −102.54, −102.56,−102.56, −102.57, −102.58, −102.60, −117.46, −117.48, −117.51; ESIMS m/z279 ([M+H]⁺).

2,6-Difluoro-N-(4-fluorophenyl)-3-nitrobenzamide (C163)

Isolated as a light-orange solid (0.178 g, 93%): mp 158-160° C.; ¹H NMR(500 MHz, DMSO-d₆) δ 11.05 (s, 1H), 8.43 (td, J=9.0, 5.6 Hz, 1H),7.76-7.65 (m, 2H), 7.56 (ddd, J=9.5, 8.0, 1.5 Hz, 1H), 7.25 (t, J=8.9Hz, 2H); ¹⁹F NMR (471 MHz, DMSO-d₆) δ −102.47, −102.48, −102.49,−102.50, −102.50, −102.52, −117.37, −117.39, −117.40, −117.41, −117.42,−117.43, −117.44; ESIMS m/z 297 ([M+H]⁺).

N-(4-Acetamidophenyl)-2,6-difluoro-3-nitrobenzamide (C164)

Isolated as a white solid (0.041 g, 19%): mp 251-255° C.; ¹H NMR (500MHz, DMSO-d₆) δ 10.90 (s, 1H), 9.97 (s, 1H), 8.41 (td, J=9.0, 5.6 Hz,1H), 7.59 (s, 4H), 7.54 (ddd, J=9.3, 7.9, 1.4 Hz, 1H), 2.04 (s, 3H); ¹⁹FNMR (471 MHz, DMSO-d₆) δ −102.50, −102.52, −102.54, −102.55, −117.45,−117.47, −117.49; ESIMS m/z 336 ([M+H]⁺).

tert-Butyl-N-tert-butoxycarbonyl-N-[3-[(2,6-difluoro-3-nitrobenzoyl)amino]-2,6-difluorophenyl]carbamate(C165)

Isolated as a pale-yellow solid (0.165 g, 48%): mp 163-165° C.; ¹H NMR(500 MHz, DMSO-d₆) δ 10.98 (s, 1H), 8.43 (td, J=9.0, 5.6 Hz, 1H), 7.87(td, J=8.8, 5.7 Hz, 1H), 7.55 (ddd, J=9.4, 8.0, 1.4 Hz, 1H), 7.31 (td,J=9.2, 1.7 Hz, 1H), 1.40 (s, 18H); ¹⁹F NMR (471 MHz, DMSO-d₆) δ −102.41,−102.43, −102.45, −102.46, −117.12, −117.14, −117.16, −122.89, −122.91,−122.93, −127.37, −127.39; ESIMS m/z 528 ([M−H]⁻).

2,6-Dichloro-3-nitro-N-(2,2,3,3,3-pentafluoropropyl)benzamide (C166)

Isolated as a white solid (0.095 g, 64%): mp 139-142° C.; ¹H NMR (400MHz, CDCl₃) δ 7.85 (d, J=8.8 Hz, 1H), 7.50 (d, J=8.8 Hz, 1H), 6.29 (s,1H), 4.18 (td, J=14.9, 6.4 Hz, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −84.17,−121.45; ESIMS m/z 367 ([M+H]⁺).

2,6-Dichloro-N-ethyl-3-nitrobenzamide (C167)

Isolated as a yellow solid (0.108 g, 61%): mp 104-108° C.; ¹H NMR (400MHz, CDCl₃) δ 7.80 (d, J=8.7 Hz, 1H), 7.47 (d, J=8.8 Hz, 1H), 5.91 (s,1H), 3.54 (qd, J=7.3, 5.8 Hz, 2H), 1.29 (t, J=7.3 Hz, 3H); IR (thinfilm) 3253, 3086, 2980, 1819, 1645, 1564, 1518, 1344, 928, 698 cm⁻¹;ESIMS m/z 261 ([M−H]⁻).

N-Ethyl-2,6-difluoro-3-nitrobenzamide (C168)

Isolated as a yellow solid (0.108 g, 62%): mp 104-108° C.; ¹H NMR (400MHz, CDCl₃) δ 8.16 (ddd, J=9.3, 8.2, 5.5 Hz, 1H), 7.10 (ddd, J=9.4, 7.7,1.8 Hz, 1H), 6.08 (s, 1H), 3.52 (qd, J=7.3, 5.7 Hz, 2H), 1.27 (t, J=7.3Hz, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −100.08, −100.10, −114.72, −114.75;IR (thin film) 3240, 3087, 2996, 1713, 1620, 1531, 1347, 1298, 1028, 843cm⁻¹; ESIMS m/z 231 ([M+H]⁺).

2,6-Dichloro-3-nitro-N-propylbenzamide (C169)

Isolated as a yellow solid (0.158 g, 88%): mp 126-129° C.; ¹H NMR (400MHz, DMSO-d₆) δ 8.82 (t, J=5.8 Hz, 1H), 8.12 (d, J=8.8 Hz, 1H), 7.81 (d,J=8.8 Hz, 1H), 3.23 (td, J=6.9, 5.7 Hz, 2H), 1.54 (h, J=7.2 Hz, 2H),0.93 (t, J=7.4 Hz, 3H); ESIMS m/z 277 ([M+H]⁺).

2,6-Dichloro-N-(2-fluoroethyl)-3-nitrobenzamide (C170)

Isolated as a cream-colored solid (0.154 g, 84%): mp 148-150° C.; ¹H NMR(500 MHz, DMSO-d₆) δ 9.14 (t, J=5.7 Hz, 1H), 8.14 (d, J=8.8 Hz, 1H),7.82 (d, J=8.7 Hz, 1H), 4.55 (dt, J=47.4, 4.9 Hz, 2H), 3.65-3.53 (m,2H); ¹⁹F NMR (471 MHz, DMSO-d₆) δ 20.28, 20.23, 20.18, 20.12, 20.07,20.06, 20.02, 19.96; ESIMS m/z 281 ([M+H]⁺).

2,6-Dichloro-3-nitro-N-(2,2,2-trifluoroethyl)benzamide (C171)

Isolated as a pale-yellow solid (0.182 g, 88%): mp 182-184° C.; ¹H NMR(500 MHz, DMSO-d₆) δ 9.57 (t, J=6.3 Hz, 1H), 8.18 (d, J=8.7 Hz, 1H),7.85 (d, J=8.8 Hz, 1H), 4.17 (qd, J=9.7, 6.3 Hz, 2H); ¹⁹F NMR (471 MHz,DMSO-d₆) δ −70.07, −70.09, −70.11; ESIMS m/z 315 ([M−H]⁻).

2,6-Dichloro-3-nitro-N-(3,3,3-trifluoropropyl)benzamide (C172)

Isolated as a pale-yellow solid (0.186 g, 86%): mp 128-130° C.; ¹H NMR(500 MHz, DMSO-d₆) δ 9.14 (t, J=5.8 Hz, 1H), 8.15 (d, J=8.7 Hz, 1H),7.82 (d, J=8.8 Hz, 1H), 3.51 (td, J=6.8, 5.7 Hz, 2H), 2.61-2.52 (m, 2H);¹⁹F NMR (471 MHz, DMSO-d₆) δ −63.89, −63.91, −63.94; ESIMS m/z 331([M+H]⁺).

2,6-Dichloro-N-(3-chloropropyl)-3-nitrobenzamide (C173)

Isolated as a yellow solid (0.180 g, 89%): mp 116-120° C.; ¹H NMR (500MHz, DMSO-d₆) δ 8.94 (t, J=5.7 Hz, 1H), 8.14 (d, J=8.7 Hz, 1H), 7.82 (d,J=8.7 Hz, 1H), 3.72 (t, J=6.5 Hz, 2H), 3.40 (q, J=6.4 Hz, 2H), 1.98 (p,J=6.6 Hz, 2H); ESIMS m/z 311 ([M+H]⁺).

2,6-Difluoro-3-nitro-N-propylbenzamide (C174)

Isolated as a light-yellow solid (0.149 g, 95%): mp 85-88° C.; ¹H NMR(500 MHz, DMSO-d₆) δ 8.93-8.83 (m, 1H), 8.33 (td, J=9.0, 5.6 Hz, 1H),7.46 (ddd, J=9.4, 8.0, 1.5 Hz, 1H), 3.24 (td, J=6.8, 5.6 Hz, 2H), 1.52(h, J=7.2 Hz, 2H), 0.91 (t, J=7.4 Hz, 3H); ¹⁹F NMR (471 MHz, DMSO-d₆) δ−102.84, −102.85, −102.87, −102.88, −102.89, −117.84, −117.86, −117.88;ESIMS m/z 245 ([M+H]⁺).

2,6-Difluoro-N-(2-fluoroethyl)-3-nitrobenzamide (C175)

Isolated as a yellow solid (0.135 g, 82%): mp 95-99° C.; ¹H NMR (500MHz, DMSO-d₆) δ 9.20 (t, J=5.6 Hz, 1H), 8.35 (td, J=9.0, 5.6 Hz, 1H),7.47 (ddd, J=9.4, 8.0, 1.6 Hz, 1H), 4.54 (dt, J=47.5, 4.9 Hz, 2H),3.66-3.54 (m, 2H); ¹⁹F NMR (471 MHz, DMSO-d₆) δ 19.65, 19.59, 19.55,19.53, 19.49, 19.45, 19.43, 19.39, 19.33, −102.68, −102.70, −102.71,−102.71, −102.72, −102.74, −117.56, −117.58, −117.60; ESIMS m/z 249([M+H]⁺).

2,6-Difluoro-3-nitro-N-(2,2,2-trifluoroethyl)benzamide (C176)

Isolated as a white solid (0.175 g, 97%): mp 137-139° C.; ¹H NMR (500MHz, DMSO-d₆) δ 9.64 (t, J=6.3 Hz, 1H), 8.39 (td, J=9.0, 5.6 Hz, 1H),7.50 (ddd, J=9.5, 8.0, 1.5 Hz, 1H), 4.19 (qd, J=9.6, 6.3 Hz, 2H); ¹⁹FNMR (471 MHz, DMSO-d₆) δ −70.70, −70.72, −70.74, −102.73, −102.74,−102.75, −102.75, −102.76, −102.76, −102.77, −102.78, −117.46, −117.48,−117.50; ESIMS m/z 283 ([M−H]⁻).

2,6-Difluoro-3-nitro-N-(3,3,3-trifluoropropyl)benzamide (C177)

Isolated as a pale-yellow solid (0.167 g, 87%): mp 108-110° C.; ¹H NMR(500 MHz, DMSO-d₆) δ 9.18 (t, J=5.8 Hz, 1H), 8.35 (td, J=9.0, 5.6 Hz,1H), 7.47 (ddd, J=9.5, 8.1, 1.5 Hz, 1H), 3.53 (td, J=6.6, 5.6 Hz, 2H),2.60-2.51 (m, 2H); ¹⁹F NMR (471 MHz, DMSO-d₆) δ −63.83, −63.86, −63.88,−102.67, −102.69, −102.70, −102.72, −117.59, −117.61, −117.63; ESIMS m/z299 ([M+H]⁺).

2,6-Difluoro-3-nitro-N-(2,2,3,3,3-pentafluoropropyl)benzamide (C178)

Isolated as a white solid (0.177 g, 83%): mp 143-145° C.; ¹H NMR (500MHz, DMSO-d₆) δ 9.66 (t, J=6.3 Hz, 1H), 8.39 (td, J=9.0, 5.6 Hz, 1H),7.50 (ddd, J=9.5, 8.1, 1.6 Hz, 1H), 4.24 (td, J=15.2, 6.3 Hz, 2H); ¹⁹FNMR (471 MHz, DMSO-d₆) δ −83.41, −102.65, −102.66, −102.68, −102.70,−117.38, −117.40, −117.42, −120.07, −120.10, −120.14; IR (thin film)3282, 3100, 2973, 1677, 1541, 1224, 1033, 730 cm⁻¹; ESIMS m/z 333([M−H]⁻).

N-(3-Chloropropyl)-2,6-difluoro-3-nitrobenzamide (C179)

Isolated as a yellow solid (0.137 g, 77%): mp 84-87° C.; ¹H NMR (500MHz, DMSO-d₆) δ 9.00 (t, J=5.7 Hz, 1H), 8.35 (td, J=9.0, 5.6 Hz, 1H),7.47 (ddd, J=9.5, 8.0, 1.5 Hz, 1H), 3.70 (t, J=6.5 Hz, 2H), 3.41 (td,J=6.7, 5.5 Hz, 2H), 1.97 (p, J=6.6 Hz, 2H); ¹⁹F NMR (471 MHz, DMSO-d₆) δ−102.82, −102.82, −102.83, −102.84, −102.85, −117.76, −117.78, −117.81;ESIMS m/z 279 ([M+H]⁺).

tert-Butyl(3-(2-chloro-3-fluoro-5-nitrobenzamido)-2,4-difluorophenyl)carbamate(C180)

Isolated as an off-white solid (0.590 g, 100%): mp=202-204° C. (dec); ¹HNMR (400 MHz, DMSO-d₆) δ 10.63 (s, 1H), 9.06 (s, 1H), 8.51 (dd, J=8.8,2.6 Hz, 1H), 8.40 (dd, J=2.6, 1.4 Hz, 1H), 8.07 (t, J=8.3 Hz, 1H), 7.42(t, J=10.4 Hz, 1H), 1.46 (s, 9H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.72,−122.28, −123.56; ESIMS m/z 544 ([M−H]⁻).

Example 67 Preparation oftert-butyl-N-((tert-butoxy)carbonyl)-N-(4-amino-3,5-difluorophenyl)carbamate(C181)

To a solution oftert-butyl-N-((tert-butoxy)carbonyl)-(3,5-difluoro-4-nitrophenyl)carbamate(C189) (1.75 g, 4.67 mmol) in ethyl acetate (30 mL) was added 5%palladium on carbon (0.498 g, 0.234 mmol). The reaction mixture wasstirred vigorously overnight at room temperature under a balloon ofhydrogen. The reaction mixture was filtered through a pad of Celite® andwashed with ethyl acetate. The filtrates were concentrated under reducedpressure to afford the title compound as an off-white solid (1.57 g,98%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.07 (ddd, J=11.4, 8.9, 2.8 Hz, 1H),6.79 (dd, J=9.3, 2.4 Hz, 1H), 4.87 (s, 2H), 1.36 (s, 18H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −128.55, −129.75.

The following compounds were prepared in like manner to the procedureoutlined in Example 67:

tert-ButylN-(3-amino-2,6-difluoro-phenyl)-N-tert-butoxycarbonyl-carbamate (C182)

Isolated as a white solid (5.06 g, 100%): ¹H NMR (400 MHz, DMSO-d₆) δ6.87 (td, J=9.3, 1.7 Hz, 1H), 6.74 (td, J=9.4, 5.7 Hz, 1H), 5.12 (s,2H), 1.39 (s, 18H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −137.96 (d, J=3.7 Hz),−141.10 (d, J=3.7 Hz); ESIMS m/z 244 ([M−BOC]⁻).

tert-Butyl-N-((tert-butoxy)carbonyl)-N-(5-amino-2,4-difluorophenyl)carbamate(C183)

Isolated as a cream colored solid (1.05 g, 88%): ¹H NMR (400 MHz, CDCl₃)δ 6.82 (dd, J=10.5, 9.3 Hz, 1H), 6.60 (dd, J=9.1, 7.5 Hz, 1H), 3.59 (s,2H), 1.43 (s, 18H); ¹⁹F NMR (376 MHz, CDCl₃) δ −131.04 (t, J=2.2 Hz),−131.38 (d, J=2.0 Hz); ESIMS m/z 245 ([M−CH₉O₂+H]⁺).

tert-Butyl (4-amino-3-methylphenyl)carbamate (C184)

Isolated as a light pink solid (12.4 g, 87%): ¹H NMR (400 MHz, DMSO-d₆)δ 8.72 (s, 1H), 7.01 (s, 1H), 6.93 (d, J=8.5 Hz, 1H), 6.49 (d, J=8.4 Hz,1H), 4.49 (s, 2H), 2.00 (s, 3H), 1.44 (s, 9H); ESIMS m/z 223 ([M+H]⁺).

tert-Butyl-N-((tert-butoxy)carbonyl(4-amino-2,6-difluorophenyl)carbamate (C185)

Isolated as an off-white solid (1.5 g, 73%): ¹H NMR (400 MHz, DMSO-d₆) δ6.28-6.18 (m, 2H), 5.83 (s, 2H), 1.37 (s, 18H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −122.91; ESIMS m/z 345 ([M+H]⁺).

N-(3-Amino-2,6-difluorophenyl)-2,2-difluoroacetamide (C186)

Isolated as a light brown solid (0.91 g, 98%): ¹H NMR (400 MHz, DMSO-d₆)δ 10.50 (s, 1H), 6.88 (td, J=9.3, 1.9 Hz, 1H), 6.72 (td, J=9.3, 5.5 Hz,1H), 6.49 (t, J=53.2 Hz, 1H), 5.58 (s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−125.61, −135.65 (d, J=3.4 Hz), −138.69 (d, J=3.5 Hz); EIMS m/z 222.

N-(3-Amino-2,6-difluorophenyl)-2,2-difluoro-N-methylacetamide (C187)

Isolated as a light yellow oil (0.26 g, 96%): ¹H NMR (400 MHz, DMSO-d₆)δ rotamers 7.00 (td, J=9.3, 1.7 Hz, 1H), 6.85 (td, J=9.4, 5.7 Hz, 1H),6.24 (t, J=52.1 Hz, 1H), 5.32 (s, 2H), 3.33 (d, J=2.7 Hz, 3H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ rotamers −124.15 (dd, J=16.1, 2.9 Hz),−137.89-−138.92 (m), −140.84-−141.99 (m); EIMS m/z 236.

tert-Butyl(3-(5-amino-2-chloro-3-fluorobenzamido)-2,4-difluorophenyl)carbamate(C188)

Isolated as a tan powder (0.563 g, 100%): ¹H NMR (400 MHz, CDCl₃) δ 8.99(t, J=8.5 Hz, 1H), 8.08 (br s, 1H), 6.97-6.89 (m, 2H), 6.59 (dd, J=10.4,2.7 Hz, 1H), 6.55 (br s, 1H), 3.98 (br s, 2H), 1.54 (s, 9H); ¹⁹F NMR(376 MHz, CDCl₃) δ −112.06, −131.58, −132.13; ESIMS m/z 414 ([M−H]⁻).

Example 68 Preparation oftert-Butyl-N-((tert-butoxy)carbonyl)-(3,5-difluoro-4-nitrophenyl)carbamate(C189)

To a solution of 3,5-difluoro-4-nitroaniline (1.0 g, 5.74 mmol) indichloromethane (25.0 mL) was added di-tert-butyl dicarbonate (2.63 g,12.1 mmol) followed by 4-dimethylaminopyridine (0.070 g, 0.574 mmol).The reaction mixture was stirred for 48 hours at room temperature. Thereaction mixture was quenched with water and poured through a phaseseparator. The organic layer was concentrated. Purification by flashcolumn chromatography using 0-20% ethyl acetate/hexanes as eluentafforded the title compound as a yellow solid (1.79 g, 83%): ¹H NMR (400MHz, CDCl₃) δ 7.04 (ddd, J=9.7, 8.0, 2.7 Hz, 1H), 6.90 (ddd, J=8.2, 2.7,1.9 Hz, 1H), 1.43 (s, 18H); ¹⁹F NMR (376 MHz, CDCl₃) δ −133.35 (d,J=23.5 Hz), −137.44 (d, J=23.4 Hz); ESIMS m/z 375 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 68:

tert-Butyl-N-((tert-butoxy)carbonyl)-N-(2,6-difluoro-3-nitrophenyl)carbamate(C190)

Isolated as a white foam (5.2 g, 69%): ¹H NMR (300 MHz, CDCl₃) δ 8.14(ddd, J=9.2, 8.1, 5.5 Hz, 1H), 7.10 (ddd, J=9.7, 8.0, 2.0 Hz, 1H), 1.45(s, 18H); ¹⁹F NMR (376 MHz, CDCl₃) δ −105.95 (dd, J=10.9, 2.7 Hz),−119.53 (d, J=10.6 Hz); ESIMS m/z 397 ([M+Na]⁺).

tert-Butyl-N-((tert-butoxy)carbonyl)-N-(2,4-difluoro-5-nitrophenyl)carbamate(C191)

Isolated as a white solid (1.2 g, 56%): ¹H NMR (400 MHz, CDCl₃) δ 8.05(t, J=7.7 Hz, 1H), 7.11 (dd, J=10.2, 8.9 Hz, 1H), 1.46 (s, 18H); ¹⁹F NMR(376 MHz, CDCl₃) δ −105.08 (dd, J=14.8, 2.2 Hz), −111.35 (dd, J=14.6,2.3 Hz); ESIMS m/z 397 ([M+Na]⁺).

tert-Butyl-N-((tert-butoxy)carbonyl)-(2,6-difluoro-4-nitrophenyl)carbamate(C192)

Isolated as a light yellow solid (2.0 g, 84%): ¹H NMR (400 MHz, DMSO-d₆)δ 8.33-8.24 (m, 2H), 1.40 (s, 18H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−115.68; ESIMS m/z 374 ([M−H]⁻).

Example 69 Preparation ofN-(2,6-difluoro-3-nitrophenyl)-2,2-difluoroacetamide (C193)

To a solution of 2,6-difluoro-3-nitroaniline (1.00 g, 5.74 mmol) indichloromethane (2.0 mL) stirred at room temperature was addedtriethylamine (1.20 mL, 8.62 mmol) and 2,2-difluoroacetic anhydride(1.30 g, 7.47 mmol). The reaction mixture was stirred at roomtemperature for 18 hours. The mixture was then loaded onto a Celite®cartridge and purified by column chromatography using 0-40% ethylacetate/hexanes as eluent to afford the title compound as a white solid(1.50 g, 100% yield): ¹H NMR (400 MHz, DMSO-d₆) δ 11.07 (s, 1H), 8.29(ddd, J=9.5, 8.4, 5.5 Hz, 1H), 7.53 (td, J=9.2, 1.9 Hz, 1H), 6.59 (t,J=53.0 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −105.42 (d, J=10.7 Hz),−120.10 (d, J=10.6 Hz), −125.98; EIMS m/z 252.

Example 70 Preparation of N-(3-amino-2-chloro-6-fluorophenyl)acetamide(C194)

Step 1: Preparation of N-(2-chloro-6-fluorophenyl)acetamide. Aceticanhydride (10 g, 99 mmol) was added dropwise to a stirred solution of2-chloro-6-fluoroaniline (12.5 g, 86 mmol), in glacial acetic acid (50mL). The resulting gold solution was heated at 90° C. for 2 hours, thencooled and quenched with water (500 mL). The resulting solid wascollected by vacuum filtration, washed with water (100 mL) and hexanes(100 mL) and dried in vacuo at 40° C. to a constant weight to give thetitle compound as a tan solid (14.87 g, 88%): ¹H NMR (400 MHz, CDCl₃) δ7.86 (s, 1H), 7.05 (dt, J=63.2, 8.4 Hz, 3H), 2.13 (s, 3H); ESIMS m/z 188([M+H]⁺).

Step 2: Preparation of N-(2-chloro-6-fluoro-3-nitrophenyl)acetamide.Sodium nitrate (4.53 g, 53.3 mmol) dissolved in water (5 mL) was addeddropwise to a stirred solution of N-(2-chloro-6-fluorophenyl)acetamide(5 g, 26.7 mmol), in concentrated sulfuric acid (10 mL) at −10° C. Uponcompletion of the addition, the resulting yellow solution was stirred at0° C. for 30 minutes, then warmed to and stirred at room temperature foranother 12 hours. The reaction mixture was poured into water (˜250 mL)and the resulting solid was collected by vacuum filtration.Recrystallization from acetonitrile gave the title compound as a lighttan solid (3.2 g, 49%): ¹H NMR (400 MHz, DMSO-d₆) δ 10.07 (s, 1H), 8.12(dd, J=9.2, 5.0 Hz, 1H), 7.70-7.55 (m, 1H), 2.12 (s, 3H); ESIMS m/z 233([M+H]⁺).

Step 3: Preparation of N-(3-amino-2-chloro-6-fluorophenyl)acetamide.Iron powder (325 mesh; 2.16 g, 38.7 mmol) was added to a stirredsolution of ethanol (50 mL) and concentrated hydrochloric acid (0.37 mL,3.87 mmol). The suspension was heated at 65° C. for 1 hour and thencooled to 55° C. A solution of ammonium chloride (1.49 g, 27.0 mmol) inwater (5 mL) was added, followed byN-(2-chloro-6-fluoro-3-nitrophenyl)acetamide (1.8 g, 7.74 mmol). Thereaction mixture was heated to 60° C. for 8 hours, cooled, and filteredthrough a pad of Celite®. The filtrate was extracted with ethyl acetate(3×50 mL). The combined organic extracts were washed with water andbrine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under reduced pressure on a rotary evaporator. Purificationby silica gel flash chromatography gave the title compound as a tansolid (1.2 g, 72%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.51 (s, 1H), 6.96 (t,J=9.2 Hz, 1H), 6.71 (dd, J=9.0, 5.1 Hz, 1H), 5.23 (s, 2H), 2.03 (s, 3H);ESIMS m/z 203 ([M+H]⁺).

Example 71 Preparation of 3-amino-2,6-difluorophenyl acetate (C195)

3-Amino-2,6-difluorophenol (0.074 g, 0.51 mmol) and4-dimethylaminopyridine (0.005 g, 0.042 mmol) were dissolved inmethylene chloride (2 mL) and the resulting solution was cooled in anice bath under nitrogen. Acetic anhydride (0.042 mL, 0.446 mmol) andtriethylamine (0.062 mL, 0.446 mmol) were added via syringe withstirring. After three hours, analysis by thin layer chromatography (1:1hexanes-ethyl acetate) indicated complete conversion. The reactionmixture was concentrated, loaded directly onto a flash silica gel columnand eluted with 4:1 hexanes-ethyl acetate to give the title compound asa sticky orange solid (0.071 g, 89%): ¹H NMR (400 MHz, CDCl₃) δ 6.78(td, J=9.2, 2.2 Hz, 1H), 6.58 (td, J=9.1, 5.0 Hz, 1H), 3.63 (br s, 2H),2.37 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −140.23 (d, J=1.6 Hz), −146.77(d, J=1.9 Hz); EIMS m/z 187.

Example 72 Preparation of 5-amino-2-chloro-3-fluorobenzoic acid (C196)

To a solution of 2-chloro-3-fluoro-5-nitrobenzoic acid (C206) (5 g, 22.8mmol) in ethyl acetate (150 mL) was added 5% platinum on carbon (0.5 g,10% w/w) and the reaction mixture was stirred under hydrogen gas (15psi) for 24 hours. The reaction mixture was carefully filtered through apad of Celite®, the pad washed with 50% ethyl acetate in methanol, andthe filtrate concentrated under reduced pressure. The crude product wastriturated with diethyl ether to afford the title compound as a paleyellow solid (2.1 g, 50%): mp 187-189° C.; ¹H NMR (400 MHz, DMSO-d₆) δ13.28 (br s, 1H), 6.81 (dd, J=1.2, 2.4 Hz, 1H), 6.61 (dd, J=2.4, 12.0Hz, 1H), 5.77 (br s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −114.65; ESIMSm/z 190 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 72:

5-Amino-2-chloro-3-(trifluoromethyl)benzoic acid (C197)

Isolated as a brown solid (3.2 g, 68%): mp 195-197° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 7.18-7.08 (m, 1H), 7.06-7.02 (m, 1H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −61.21; ESIMS m/z 240 ([M+H]⁺).

5-Amino-2-chloro-3-methylbenzoic acid (C198)

Isolated as a brown solid (3.2 g, 72%): mp 190-192° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 12.82 (br s, 1H), 6.76 (d, J=2.4 Hz, 1H), 6.67 (d, J=2.4,1H), 2.22 (s, 3H); ESIMS m/z 186 ([M+H]⁺).

5-Amino-2,3-difluorobenzoic acid (C199)

Isolated as a brown solid (2.5 g, 60%): mp 211-213° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 13.20 (br s, 1H), 6.84-6.78 (m, 1H), 6.74-6.64 (m, 1H), 5.46(br s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −138.22, −155.42; ESIMS m/z 174([M+H]⁺).

5-Amino-3-chloro-2-fluorobenzoic acid (C200)

Isolated as a brown solid (4.0 g, 66%): mp 205-207° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 13.40 (br s, 1H), 7.02-6.94 (m, 1H), 6.92-6.84 (m, 1H), 5.48(br s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −132.31; ESIMS m/z 190([M+H]⁺).

5-Amino-2-fluoro-3-methylbenzoic acid (C201)

Isolated as a brown solid (5.2 g, 76%): mp 206-208° C.; ¹H NMR (300 MHz,DMSO-d₆) δ 12.82 (br s, 1H), 6.88-6.80 (m, 1H), 6.68-6.58 (m, 1H), 5.28(br s, 2H), 2.12 (s, 3H); ¹⁹F NMR (282 MHz, DMSO-d₆) δ −132.24; ESIMSm/z 170 ([M+H]⁺).

5-Amino-3-chloro-2-methylbenzoic acid (C202)

Isolated as an off-white solid (1.3 g, 65%): mp 192-194° C.; ¹H NMR (400MHz, DMSO-d₆) δ 12.82 (br s, 1H), 6.93 (d, J=2.1 Hz, 1H), 6.78 (d, J=2.4Hz, 1H), 5.37 (br s, 2H), 2.31 (s, 3H); ESIMS m/z 186 ([M+H]⁺).

5-Amino-3-fluoro-2-methylbenzoic acid (C203)

Isolated as a brown solid (0.3 g, 55%): mp 164-166° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 12.82 (br s, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.48 (dd, J=2.0,8.0 Hz, 1H), 5.36 (br s, 2H), 2.19 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−116.94; ESIMS m/z 170 ([M+H]⁺).

5-Amino-3-chloro-2-methoxybenzoic acid (C204)

Isolated as a brown solid (2.5 g, 75%): mp 173-175° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 12.8 (br s, 1H), 6.84 (d, J=2.8 Hz, 1H), 6.79 (d, J=2.8 Hz,1H), 5.62 (br s, 2H), 3.68 (s, 3H); ESIMS m/z 202 ([M+H]⁺).

5-Amino-3-fluoro-2-methoxybenzoic acid (C205)

Isolated as a pale yellow solid (6.01 g, 85%): mp 148-150° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 12.82 (br s, 1H), 6.72-6.66 (m, 1H), 6.55 (dd,J=2.0, 13.6 Hz, 1H), 5.40 (br s, 2H), 3.69 (s, 3H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −131.02; ESIMS m/z 186 ([M+H]⁺).

Example 73 Preparation of 2-chloro-3-fluoro-5-nitrobenzoic acid (C206)

To a suspension of 2-chloro-3-fluorobenzoic acid (10 g, 57.5 mmol) inconcentrated sulfuric acid (62 mL, 1149.5 mmol) was added concentratednitric acid (4 mL, 86.2 mmol) dropwise at −10° C. and the reactionmixture was stirred between −10° C. and 0° C. for 3 hours. The reactionmixture was slowly poured into a beaker of crushed ice (˜1 L), and theresulting precipitated solid was filtered and washed with water (100mL). The crude product was recrystallized from hot water to afford thetitle compound as an off-white solid (7.5 g, 60%): mp 163-165° C.; ¹HNMR (400 MHz, DMSO-d₆) δ 14.60-13.92 (br s, 1H), 8.53 (dd, J=2.8, 8.8Hz, 1H), 8.44-8.41 (m, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −108.50; ESIMSm/z 218 ([M−H]⁻).

The following compounds were prepared in like manner to the procedureoutlined in Example 73:

2-Chloro-5-nitro-3-(trifluoromethyl)benzoic acid (C207)

The title compound was recrystallized from hot water to give a brownsolid (9 g, 80%): mp 165-167° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (d,J=2.8 Hz, 1H), 8.61 (d, J=2.8 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−61.72; ESIMS m/z 268 ([M−H]⁻).

2-Chloro-3-methyl-5-nitrobenzoic acid (C208)

The title compound was precipitated from a diethyl ether solution withn-pentane to give an off-white solid (8.2 g, 65%): mp 205-207° C.; ¹HNMR (300 MHz, DMSO-d₆) δ 8.41 (d, J=2.4 Hz, 1H), 8.34 (d, J=3.0 Hz, 1H),2.24 (s, 3H); ESIMS m/z 214 ([M−H]⁻).

2,3-Difluoro-5-nitrobenzoic acid (C209)

The title compound was recrystallized from hot water to give anoff-white solid (5.2 g, 40%): mp 132-134° C.; ¹H NMR (300 MHz, DMSO-d₆)δ 14.60-13.80 (br s, 1H), 8.74-8.62 (m, 1H), 8.52-8.40 (m, 1H); ¹⁹F NMR(282 MHz, DMSO-d₆) δ −125.36, −132.16; ESIMS m/z 202 ([M−H]⁻).

3-Chloro-2-fluoro-5-nitrobenzoic acid (C210)

The title compound was recrystallized from hot water to give anoff-white solid (6.9 g, 55%): mp 186-188° C.; ¹H NMR (400 MHz, DMSO-d₆)δ 14.40-13.80 (br s, 1H), 8.78-8.70 (m, 1H), 8.58-8.48 (m, 1H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −102.78; ESIMS m/z 218 ([M−H]⁻).

2-Fluoro-3-methyl-5-nitrobenzoic acid (C211)

The title compound was precipitated from a methanol solution with waterto give a pale brown solid (7.5 g, 58%): mp 168-170° C.; ¹H NMR (300MHz, DMSO-d₆) δ 13.88 (br s, 1H) 8.48-8.40 (m, 2H), 2.41 (s, 3H); ¹⁹FNMR (376 MHz, DMSO-d₆) δ −106.64; ESIMS m/z 198 ([M−H]⁻).

3-Chloro-2-methoxy-5-nitrobenzoic acid (C212)

Note: The reaction solvent used was a mixture of sulfuric acid andacetic acid (1:1), and the title compound was recrystallized from hotwater and isolated as an off-white solid (9.3 g, 75%): mp 155-157° C.;¹H NMR (300 MHz, DMSO-d₆) δ 8.54 (d, J=2.4 Hz, 1H), 8.42 (d, J=2.4 Hz,1H), 3.96 (s, 3H); ESIMS m/z 232 ([M−H]⁻).

3-Fluoro-2-methoxy-5-nitrobenzoic acid (C213)

Note: The reaction solvent used was a mixture of sulfuric acid andacetic acid (1:1), and the title compound was recrystallized from hotwater and isolated as an off-white solid (9.1 g, 70%): mp 106-108° C.;¹H NMR (400 MHz, DMSO-d₆) δ 13.62 (br s, 1H), 8.40 (dd, J=2.8, 10.8 Hz,1H), 8.32-8.28 (m, 1H), 4.04 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−125.26; ESIMS m/z 216 ([M+H]⁺).

Example 74 Preparation of methyl 3-chloro-2-methyl-5-nitrobenzoate(C214)

Step 1: Preparation of 3-chloro-2-methyl-5-nitrobenzoic acid. To asuspension of 3-chloro-2-methylbenzoic acid (10 g, 57.5 mmol) inconcentrated sulfuric acid (48 mL, 867 mmol) was added concentratednitric acid (2.5 mL, 68.4 mmol) dropwise at −10° C. and the reactionmixture was stirred between −10° C. and 0° C. for 3 hours. The reactionmixture was slowly poured into a beaker of crushed ice (˜1 L), and theprecipitated solid was collected by filtration and washed with water(100 mL). The crude product was recrystallized from hot water to give amixture of 3-chloro-2-methyl-5/6-nitrobenzoic acid as a brown solid (7.5g), which was used without any purification: ESIMS m/z 214 ([M−H]⁻).

Step 2: Preparation of methyl 3-chloro-2-methyl-5-nitrobenzoate. To astirred solution of 3-chloro-2-methyl-5/6-nitrobenzoic acid (6 g, 28mmol) in methanol (100 mL) was added thionyl chloride at ambienttemperature, and the reaction mixture was stirred at 80° C. for 4 hours.The reaction mixture was concentrated under reduced pressure.Purification by silica gel column chromatography using 20-30% ethylacetate in petroleum ether as eluent gave the title compound (1.5 g; 12%yield over two steps) as a pale-yellow solid: ¹H NMR (400 MHz, CDCl₃) δ8.58 (d, J=2.4 Hz, 1H), 8.37 (d, J=2.4 Hz, 1H), 3.97 (s, 3H), 2.72 (s,3H); ESIMS m/z 228 ([M−H]⁻).

The following compounds were prepared in like manner to the procedureoutlined in Example 74:

Methyl 3-fluoro-2-methyl-5-nitrobenzoate (C215)

Isolated as a pale-yellow solid (1 g, 10% yield over two steps): ¹H NMR(300 MHz, CDCl₃) δ 8.58 (s, 1H), 8.04 (dd, J=2.4, 9.0 Hz, 1H), 3.97 (s,3H), 2.61 (d, J=2.4, 3H); ESIMS m/z 214 ([M+H]⁺).

Example 75 Preparation of 3-chloro-2-methyl-5-nitrobenzoic acid (C216)

To a stirred solution of methyl 3-chloro-2-methyl-5-nitrobenzoate (C214)(1.5 g, 6.5 mmol) in a mixture of tetrahydrofuran, methanol, and water(2:1:2; 20 mL total) was added lithium hydroxide-monohydrate (0.820 g,19.5 mmol), and the reaction mixture was stirred at ambient temperaturefor 16 hours. The reaction mixture was concentrated under reducedpressure, and the residue was dissolved in water (20 mL) and acidifiedwith 2 N hydrochloric acid (10 mL; pH=1-2). The resulting precipitatedsolid was collected by filtration, washed with water (50 mL), and driedunder vacuum to afford the title compound (1 g, 71%) as an off-whitesolid: mp 176-178° C.; ¹H NMR (300 MHz, DMSO-d₆) δ 13.9 (br s, 1H), 8.43(s, 2H), 2.64 (s, 3H); ESIMS m/z 214 ([M−H]⁻).

The following compounds were prepared in like manner to the procedureoutlined in Example 75:

3-Fluoro-2-methyl-5-nitrobenzoic acid (C217)

Isolated as an off-white solid (0.800 g, 86%): mp 146-148° C.; ¹H NMR(300 MHz, DMSO-d₆) δ 13.92 (br s, 1H), 8.37 (s, 1H), 8.25 (dd, J=2.4,9.3 Hz, 1H), 2.50 (d, J=2.1 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−110.64; ESIMS m/z 198 ([M−H]⁻).

Example 76 Preparation of2-chloro-N,N′-dimethyl-5-nitro-N′-phenylbenzohydrazide (C218)

To a solution of 2-chloro-N′-methyl-5-nitro-N′-phenylbenzohydrazide(C219) (0.273 g, 0.893 mmol) in N,N-dimethylformamide (8.5 mL) cooled to0° C. was added sodium hydride (60% oil immersion, 0.045 g, 1.116 mmol).The reaction mixture was allowed to stir at 0° C. for 15 minutes andthen methyl iodide (0.070 mL, 1.116 mmol) was added. The reactionmixture was allowed to warm to room temperature and was stirred for 3hours. The reaction was quenched with water (10 mL) and extracted withethyl acetate (25 mL). The organic layer was washed with water (3×15 mL)and brine (15 mL) and then concentrated under reduced pressure to affordthe title compound as a yellow solid (0.283 g, 98%): ¹H NMR (400 MHz,CDCl₃) δ 8.13 (d, J=2.6 Hz, 1H), 8.08 (dd, J=8.8, 2.6 Hz, 1H), 7.53 (d,J=8.8 Hz, 1H), 7.32 (dd, J=8.9, 7.3 Hz, 2H), 6.95 (tt, J=7.3, 1.1 Hz,1H), 6.75 (dt, J=7.9, 1.1 Hz, 2H), 3.20 (s, 3H), 3.11 (s, 3H); IR (thinfilm) 3074, 2925, 1662, 1524, 1494, 1345, 869, 741 cm⁻¹; ESIMS m/z 320([M+H]⁺).

Example 77 Preparation of2-chloro-N′-methyl-5-nitro-N′-phenylbenzohydrazide (C219)

To a solution of 2-chloro-5-nitrobenzoic acid (0.300 g, 1.49 mmol) and1-methyl-1-phenylhydrazine (0.282 g, 2.31 mmol) in ethyl acetate (5.0mL) stirred at room temperature were added pyridine (0.235 g, 2.98 mmol)and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide(T3P®) as a 50% solution in ethyl acetate (1.421 g, 2.23 mmol). Thereaction mixture was stirred at room temperature for 48 hours. Thereaction mixture was diluted with ethyl acetate (20 mL). The organicphase was washed with 1 M aqueous hydrochloric acid (15 mL), water (2×10mL), and brine (10 mL) and was concentrated under reduced pressure.Purification by column chromatography using 0-35% ethyl acetate/hexanesas eluent afforded the title compound as a pale yellow solid (0.273 g,60%): ¹H NMR (400 MHz, CDCl₃) ¹H NMR (400 MHz, DMSO-d₆) δ 10.71 (s, 1H),8.47 (d, J=2.8 Hz, 1H), 8.34 (dd, J=8.8, 2.8 Hz, 1H), 7.89 (d, J=8.8 Hz,1H), 7.41-7.17 (m, 2H), 6.94 (dt, J=7.7, 1.0 Hz, 2H), 6.87-6.52 (m, 1H),3.24 (s, 3H); IR (thin film) 3207, 3064, 2967, 2807, 1670, 1538, 1351,737 cm⁻¹; ESIMS m/z 306 ([M+H]⁺).

Example 78 Preparation of1-methyl-2-(3,3,3-trifluoropropylidene)hydrazine (C220)

To a solution of 3,3,3-trifluoropropanal (0.600 g, 5.4 mmol) in ethanol(12 mL) was added methyl hydrazine (0.493 g, 10.8 mmol) and acetic acid(0.1 mL) at 0° C. The reaction mixture was stirred at room temperaturefor 16 hours. The reaction mixture was poured into water (20 mL) andextracted with diethyl ether (2×20 mL). The organic layer was dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to afford the title compound (crude) as a brown liquid (0.600g): ¹H NMR (300 MHz, CDCl₃) δ 6.67 (t, J=5.6 Hz, 1H), 5.34-5.30 (m, 1H),3.10-2.96 (m, 2H), 2.83 (s, 3H).

Example 79 Preparation of5-amino-N-(3-amino-2,4-difluorophenyl)-2-chlorobenzamide hydrochloride(C221)

A 4 M solution of hydrochloric acid in 1,4-dioxane (4.5 mL, 18 mmol) wasadded to a stirred solution oftert-butyl-N-((tert-butoxy)carbonyl)-N-(3-(5-amino-2-chlorobenzamido)-2,6-difluorophenyl)carbamate(C135) in dichloromethane (18 mL) at 23° C. The resulting thickoff-white mixture was stirred at 23° C. for 18 hours. The reactionmixture was concentrated by rotary evaporation to afford the titlecompound as an off-white powder (0.660 g, 99% crude yield): ¹H NMR (400MHz, DMSO-d₆) δ 10.16 (s, 1H), 7.47 (d, J=8.5 Hz, 1H), 7.23 (br s, 1H),7.17 (br d, J=8.5 Hz, 1H), 6.90 (td, J=10, 1.2 Hz, 1H), 6.80 (m, 1H);ESIMS m/z 298 ([M+H]⁺).

Example 80 Preparation of2-chloro-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-5-nitrobenzamide(C222)

To a solution of N-(3-amino-2,6-difluorophenyl)-2,2-difluoroacetamide(C186) (0.455 g, 2.05 mmol) in ethyl acetate (7 mL) was added sodiumbicarbonate (0.344 g, 4.10 mmol) and 2-chloro-5-nitrobenzoyl chloride(0. 451 mg, 2.05 mmol). The reaction mixture was stirred for 3 hours atroom temperature. The reaction mixture was diluted with ethyl acetateand washed with water (15 mL). The organic layer was passed through aphase separator to dry and concentrated to afford the title compound asa white solid (0.55 g, 66%): ¹H NMR (400 MHz, DMSO-d₆) δ 10.80 (s, 1H),10.69 (s, 1H), 8.50 (d, J=2.7 Hz, 1H), 8.35 (dd, J=8.8, 2.8 Hz, 1H),7.94-7.80 (m, 2H), 7.31 (td, J=9.3, 1.8 Hz, 1H), 6.55 (t, J=53.2 Hz,1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −120.61 (d, J=2.6 Hz), −124.72 (d,J=2.7 Hz), −125.81; ESIMS m/z 406 ([M+H]⁺).

Example 81 Preparation of tert-butyl (3-methyl-4-nitrophenyl)carbamate(C223)

N,N-Dimethylpyridin-4-amine (2.41 g, 19.72 mmol) was added portionwiseto a stirring solution of 3-methyl-4-nitroaniline (15 g, 99 mmol) anddi-tert-butyl dicarbonate (25.8 g, 118 mmol) in dichloromethane (200mL). The resulting yellow solution was stirred at 24° C. for 18 hoursand concentrated under vacuum on a rotary evaporator. Purification bysilica gel flash chromatography with a gradient of ethyl acetate inhexane to give the title compound as a pale yellow solid (11.5 g, 44%).¹H NMR (400 MHz, CDCl₃) δ 8.04 (d, J=9.0 Hz, 1H), 7.41 (d, J=2.4 Hz,1H), 7.30 (dd, J=9.0, 2.5 Hz, 1H), 6.80 (s, 1H), 2.62 (s, 3H), 1.53 (s,9H); ¹³C NMR (101 MHz, CDCl₃) δ 151.96, 142.97, 136.22, 126.70, 120.79,115.55, 81.75, 28.22, 21.45; ESIMS m/z 253 ([M+H]⁺).

Example R1 Resolution of racemictrans-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylic acidwith (L)-leucinamide to provide(1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylicacid

A mixture of (L)-leucinamide (163 mg, 1.25 mmol) and racemictrans-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-carboxylic acid)(750 mg, 2.5 mmol) in acetonitrile (20 mL) was stirred at 60° C. for 0.5hours. After a solid began to deposit, the mixture placed at roomtemperature for 4 hours. The white solid was collected, washed withminimal acetonitrile and dried: ¹H NMR (400 MHz, DMSO-d⁶) δ 7.81 (s,1H), 7.53 (t, J=1.9 Hz, 1H), 7.43 (d, J=1.9 Hz, 2H), 7.31 (s, 1H),3.58-3.44 (m, 1H), 3.27 (d, J=8.6 Hz, 1H), 3.08 (d, J=8.6 Hz, 1H), 1.68(dt, J=13.3, 6.6 Hz, 1H), 1.49 (dt, J=10.1, 6.8 Hz, 2H), 0.89 (t, J=6.7Hz, 6H).

The white solid salt was diluted with EtOAc and washed with 1N HCl andbrine solution. The organic layer was dried over Na₂SO₄, filtered andconcentrated to afford the title product as a white solid: (0.202 g, 91%ee, 27% yield); ¹H NMR (300 MHz, CDCl₃) δ 7.36 (t, J=1.9 Hz, 1H), 7.17(dd, J=1.9, 0.7 Hz, 2H), 3.48-3.37 (m, 1H), 2.87 (d, J=8.3 Hz, 1H). ¹³CNMR (400 MHz, DMSO-d⁶) δ 166.28, 136.40, 133.39, 127.27, 127.04, 61.36,37.10, 35.98. LCMS m/z=298.9 [M+H].

Example R2 Resolution of racemictrans-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxylicacid with (L)-leucinamide to provide(R,R)-trans-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxylicacid

A mixture of (L)-leucinamide (0.45 g, 3.5 mmol) and racemictrans-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-carboxylicacid) (1.41 g, 5 mmol) in acetonitrile (20 mL) was stirred at 60° C. for0.5 hours. After a solid began to deposit, the mixture was placed atroom temperature for 4 hours. The white solid was collected, washed withminimal acetonitrile and dried: 1H NMR (400 MHz, DMSO-d₆) δ 7.81 (s,1H), 7.53 t, J=1.9 Hz, 1H), 7.43 (d, J=1.9 Hz, 2H), 7.31 (s, 1H),3.58-3.44 (m, 1H), 3.27 (d, J=8.6 Hz, 1H), 3.08 (d, J=8.6 Hz, 1H), 1.68(dt, J=13.3, 6.6 Hz, 1H), 1.49 (dt, J=10.1, 6.8 Hz, 2H), 0.89 t, J=6.7Hz, 6H).

The white solid salt was diluted with EtOAc and washed with 1N HCl andbrine solution. The organic layer was dried over Na₂SO₄, filtered andconcentrated to afford the title product as a white solid: (0.64 g, 91%ee, 45% yield); 1H NMR (400 MHz, DMSO-d₆) δ 13.29 (s, 1H), 7.72 (dd,J=7.1, 2.1 Hz, 1H), 7.56-7.32 (m, 2H), 3.46 (d, J=1.0 Hz, 2H); 19F NMR(376 MHz, DMSO-d₆) δ −117.35.

Example R3 Resolution of racemictrans-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxylic acidwith (L)-leucinamide to provide(R,R)-trans-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxylicacid

A mixture of (L)-leucinamide (326 mg, 2.5 mmol) and racemictrans-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-carboxylic acid)(1.5 g, 5 mmol) in acetonitrile (20 mL) was stirred at 60° C. for 0.5hours. After a solid began to deposit, the mixture was placed at roomtemperature for 4 hours. The solid was collected, washed with minimalacetonitrile and dried: ¹H NMR (400 MHz, DMSO-d⁶) δ 7.72 (s, 1H), 7.64(d, J=2.1 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.34 (dd, J=8.4, 2.1 Hz, 1H),7.31-7.26 (m, 1H), 3.48 (dd, J=8.2, 6.2 Hz, 1H), 3.26 (d, J=8.6 Hz, 1H),3.03 (d, J=8.7 Hz, 1H), 1.74-1.57 (m, 1H), 1.47 (ddd, J=14.6, 7.7, 6.1Hz, 2H), 0.89 (t, J=6.9 Hz, 6H).

The white solid salt was diluted with EtOAc and washed with 1N HCl andbrine solution. The organic layer was dried over Na₂SO₄, filtered andconcentrated to afford the title product as a white solid: (0.56 g, 96%ee, 36% yield); ¹H NMR (500 MHz, DMSO-d⁶) δ 13.39 (s, 1H), 7.76 (d,J=2.1 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.44 (dd, J=8.4, 2.1 Hz, 1H),3.49 (s, 2H). ¹³C NMR (126 MHz, DMSO) δ 166.34, 133.35, 130.47, 130.33,130.09, 129.77, 128.81, 61.43, 37.00, 36.06. LCMS m/z=298.9 [M+H].

Example R4 Resolution of racemictrans-2,2-dichloro-3-(3-trifluoromethyl-4-fluorophenyl)cyclopropane-1-carboxylicacid with (L)-leucinamide to provide(1R,3R)-2,2-dichloro-3-(3-trifluoromethyl-4-fluorophenyl)cyclopropane-1-carboxylicacid

A mixture of (L)-leucinamide (15.6 g, 120 mmol) and racemictrans-2,2-dichloro-3-(3-trifluoromethyl-4-fluorophenyl)cyclopropane-1-carboxylicacid (63.4 g, 200 mmol) in acetonitrile (800 mL) was stirred at 60° C.for 1 hr. After a solid began to deposit, the mixture was placed at roomtemperature for 4 hours. The solid was collected, washed with minimalacetonitrile and dried to afford the salt of (L)-leucinamide andtrans-(1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylateas a white solid: (38.9 g, 95% ee, 43%); ¹H NMR (400 MHz, DMSO-d⁶) δ7.80 (s, 1H), 7.73 (m, Hz, 2H), 7.49 (dd, J=10.7, 8.6 Hz, 1H), 7.31 (s,1H), 3.53 (dd, J=7.9, 6.4 Hz, 1H), 3.34 (d, J=8.6 Hz, 1H), 3.07 (d,J=8.6 Hz, 1H), 1.77-1.60 (m, 1H), 1.60-1.40 (m, 2H), 0.89 (t, J=6.7 Hz,6H); ¹⁹F NMR (376 MHz, DMSO) δ −59.88, −117.93.

The white solid salt was diluted with EtOAc and washed with 1.5N HCl andwater. The organic layer was dried over Na₂SO₄, filtered andconcentrated to afford the title product as a white solid (27.3 g, 95%ee, 43% yield). ¹H NMR (400 MHz, DMSO-d⁶) δ 13.24 (s, 1H), 8.03-7.71 (m,2H), 7.54 (dd, J=10.6, 8.7 Hz, 1H), 3.65-3.51 (m, 2H); ¹⁹F NMR (376 MHz,DMSO-d⁶) δ −59.93, −117.06; LCMS m/z=316 [M−H].

Example R5 Resolution of racemictrans-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid with (R)-2-amino-3-phenylpropanamide ((D)-phenylalanine) to provide(R)-2-amino-3-phenylpropanamide(1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylate

In a flask with a magnetic stirrer, a mixture of2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (1.58 g, 5.0 mmol) and (R)-2-amino-3-phenylpropanamide (411 mg, 2.5mmol) in acetonitrile (20 mL) was heated to 60° C. The resultingsuspension was stirred at 60° C. for 10 min, then cooled to RT. Themixture was stirred overnight. The product was filtered and washed withacetonitrile, then dried in air and at 35° C. in a vacuum oven to give(R)-2-amino-3-phenylpropanamide(1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylate(710 mg, 1.475 mmol, 29.5% yield) as a white solid. Chiral HPLC analysisindicated the ratio of SS/RR was 6/93 (86% ee).

Example R6 Resolution of racemictrans-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid with (S)-2-amino-3-phenylpropanamide to provide(S)-2-amino-3-phenylpropanamide(15,3S)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylate

In a flask with a magnetic stirrer, a mixture of racemic2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (1.58 g, 5.0 mmol) and (S)-2-amino-3-phenylpropanamide (411 mg, 2.5mmol) in acetonitrile (ACN, 20 mL) was heated to 60° C. The resultingsuspension was stirred at 60° C. for 10 min, then cooled to rt. Themixture was stirred overnight. The product was filtered and washed withACN, then dried in air and at 35° C. in a vacuum oven to give(S)-2-amino-3-phenylpropanamide(15,3S)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylate(0.669 g, 1.390 mmol, 27.8% yield) as a white solid. The chiral HPLCindicated the ratio of SS/RR was 96/3 (93% ee).

The following compounds were prepared in like manner to the procedureoutlined in Example 1:

trans-5-(3-(3-Bromo-4-chlorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1358)

Isolated as a white solid (0.140 g, 63%).

trans-5-(3-(3-Bromo-4-chlorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1359)

Isolated as a white solid (0.098 g, 56%).

trans-2-Chloro-N-(4-chloro-3-(2,2,2-trifluoroacetamido)phenyl)-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1366)

Isolated as a white solid (0.076 g, 80%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(3,5-dichloro-4-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1368)

Isolated as a white solid (0.069 g, 76%).

trans-2-Chloro-N-(3-chloro-4-(2,2,2-trifluoroacetamido)phenyl)-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1384)

Isolated as a white solid (0.093 g, 70%).

trans-2-Chloro-N-(3-cyano-4-(2,2,2-trifluoroacetamido)phenyl)-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1388)

Isolated as a yellow foam (0.039 g, 72%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,3-dimethyl-4-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1392)

Isolated as a white foam (0.055 g, 80%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(4-(2,2,2-trifluoroacetamido)-3-(trifluoromethyl)phenyl)benzamide(F1393)

Isolated as a white foam (0.078 g, 75%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)benzamide(F1394)

Isolated as a white foam (0.078 g, 75%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2-methyl-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1451)

Isolated as a white solid (0.087 g, 75%).

5-((1R,3R)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-2-fluorobenzamide(F1491)

Isolated as a white solid (0.086 g, 76%).

5-((1R,3R)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-2-fluorobenzamide(F1492)

Isolated as a white solid (0.102 g, 87%).

5-((1R,3R)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)-2-fluorobenzamide(F1509)

Isolated as a white foam (0.059 g, 51.9%).

5-((1R,3R)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)-2-fluorobenzamide(F1510)

Isolated as a tan solid (0.119 g, 85%).

trans-5-(3-(4-Bromophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1597)

Isolated as a clear, colorless oil (0.050 g, 86%).

trans-2-Chloro-5-(2,2-dichloro-3-(4-fluorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1598)

Isolated as a clear, colorless oil (0.052 g, 78%).

trans-2-Chloro-5-(2,2-dichloro-3-(4-chlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1599)

Isolated as a white foam (0.101 g, 87%).

trans-5-(3-(3-Bromophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1600)

Isolated as a clear, colorless oil (0.057 g, 80%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-chlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1601)

Isolated as a white foam (0.076 g, 75%).

trans-2-Chloro-5-(2,2-dichloro-3-(3-fluorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1602)

Isolated as a white foam (0.103 g, 83%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoro-N-methylacetamido)phenyl)benzamide(F1614)

Isolated as a white foam (0.109 g, 93%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,3,3,3-pentafluoro-N-methylpropanamido)phenyl)benzamide(F1615)

Isolated as a white foam (0.123 g, 98%).

trans-5-(3-(3-Bromo-4,5-dichlorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1623)

Isolated as a white foam (0.061 g, 68%). The title compound was preparedfromN-(3-amino-2,4-difluorophenyl)-5-(3-(3-bromo-4,5-dichlorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamidewhich was prepared via methods described in U.S. Patent ApplicationPublication US20160304522A1 (F621).

trans-2-Chloro-5-(2,2-dichloro-3-(4-fluoro-3-iodophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1624)

Isolated as a white solid (0.066 g, 74%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-chloro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1656)

Isolated as a white foam (0.077 g, 84%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-chloro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1657)

Isolated as a white foam (0.082 g, 91%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1675)

Isolated as a white solid (0.077 g, 86%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluoro-3-methylphenyl)benzamide(F1680)

Isolated as a white foam (0.048 g, 71%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1695)

Isolated as a yellow foam (0.094 g, 80%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,3,3,3-pentafluoropropanamido)phenyl)benzamide(F1696)

Isolated as a white foam (0.089 g, 71%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1711)

Isolated as a white solid (0.075 g, 84%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,3,4-trifluorophenyl)benzamide(F1744)

Isolated as a clear, colorless oil (0.117 g, 99%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-N-methylbenzamide(F1792)

Isolated as a white foam (0.082 g, 70%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-N-methylbenzamide(F1795)

Isolated as a light yellow oil (0.091 g, 79%).

trans-5-(3-(3,5-bis(Trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1801)

Isolated as a white solid (0.098 g, 86%).

trans-5-(3-(3,5-bis(Trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1802)

Isolated as a white solid (0.096 g, 86%).

The following compounds were prepared in like manner to the procedureoutlined in Example 2:

N-(3-Acetamido-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-2-fluorobenzamide(F1493)

Isolated as a tan solid (0.100 g, 66%).

N-(5-Acetamido-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-2-fluorobenzamide(F1511)

Isolated as a white foam (0.108 g, 84%).

N-(3-Acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-chloro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1658)

Isolated as a white solid (0.061 g, 72%).

N-(3-Acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1694)

Isolated as a white foam (0.094 g, 88%). The title compound was preparedfromN-(3-amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamidewhich was prepared using methods described in U.S. Patent ApplicationPublication US20160304522A1 (F317).

N-(3-Acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-methylbenzamide(F1799)

Isolated as a white foam (0.070 g, 65%).

trans-N-(3-Acetamido-2,4-difluorophenyl)-5-(3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamide(F1803)

Isolated as a white foam (0.062 g, 58%).

The following compounds were prepared in like manner to the procedureoutlined in Example 3:

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-3-fluorobenzamide(F1340)

Isolated as a white solid (0.050 g, 96%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)-3-fluorobenzamide(F1341)

Isolated as a yellow solid (0.052 g, 100%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-3-fluorobenzamide(F1342)

Isolated as a white solid (0.051 g, 98%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)-3-fluorobenzamide(F1343)

Isolated as an off-white solid (0.050 g, 99%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-3-fluorobenzamide(F1344)

Isolated as a white solid (0.049 g, 100%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)-3-fluorobenzamide(F1345)

Isolated as a white solid (0.047 g, 99%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-3-fluorobenzamide(F1346)

Isolated as a white solid (0.046 g, 99%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)-3-fluorobenzamide(F1347)

Isolated as an off white solid (0.045 g, 100%).

N-(3-(2-Bromo-2,2-difluoroacetamido)-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1356)

Isolated as an off white solid (0.048 g, 96%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)-3-fluorobenzamide(F1400)

Isolated as a tan solid (0.086 g, 90%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)-3-fluorobenzamide(F1401)

Isolated as a white solid (0.087 g, 89%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)-3-fluorobenzamide(F1402)

Isolated as a tan solid (0.078 g, 83%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)-3-fluorobenzamide(F1403)

Isolated as a light-tan solid (0.090 g, 93%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)-3-fluorobenzamide(F1404)

Isolated as a light-tan solid (0.085 g, 91%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)-3-fluorobenzamide(F1405)

Isolated as a white solid (0.085 g, 88%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)-3-fluorobenzamide(F1406)

Isolated as a light-tan solid (0.087 g, 94%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)-3-fluorobenzamide(F1407)

Isolated as a white solid (0.086 g, 89%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)-3-fluorobenzamide(F1408)

Isolated as a light-tan solid (0.084 g, 88%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)-3-fluorobenzamide(F1409)

Isolated as a white solid (0.087 g, 89%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)-3-methylbenzamide(F1429)

Isolated as a white solid (0.056 g, 99%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-3-methylbenzamide(F1430)

Isolated as a tan solid (0.057 g, 98%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)-3-methylbenzamide(F1431)

Isolated as a tan solid (0.058 g, 94%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-3-methylbenzamide(F1432)

Isolated as a white solid (0.060 g, 95%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)-3-methylbenzamide(F1468)

Isolated as a white solid (0.056 g, 99%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-3-methylbenzamide(F1469)

Isolated as a white solid (0.058 g, 100%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-3-methylbenzamide(F1484)

Isolated as a tan powder (0.057 g, 100%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-3-methylbenzamide(F1485)

Isolated as a tan powder (0.058 g, 100%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-3-methylbenzamide(F1486)

Isolated as a tan powder (0.062 g, 100%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-3-methylbenzamide(F1487)

Isolated as a tan powder (0.060 g, 95%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-3-methylbenzamide(F1494)

Isolated as a tan powder (0.047 g, 99%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-3-methylbenzamide(F1495)

Isolated as a tan powder (0.049 g, 99%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)-3-methylbenzamide(F1496)

Isolated as a tan powder (0.055 g, 90%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)-3-methylbenzamide(F1497)

Isolated as a tan powder (0.063 g, 100%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)-3-methylbenzamide(F1498)

Isolated as a tan powder (0.067 g, 99%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)-3-methylbenzamide(F1499)

Isolated as a tan powder (0.066 g, 95%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)-3-methylbenzamide(F1500)

Isolated as a tan powder (0.056 g, 99%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)-3-methylbenzamide(F1501)

Isolated as a tan powder (0.057 g, 99%).

N-(3-Acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1502)

Isolated as a tan powder (0.039 g, 52%).

N-(3-Acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1504)

Isolated as a tan powder (0.071 g, 44%).

The following compounds were prepared in like manner to the procedureoutlined in Example 4:

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,3,3-tetrafluoropropanamido)phenyl)benzamide(F1414)

Isolated as a white foam (0.104 g, 85%).

2-Chloro-N-(2,4-dichloro-3-(2-cyanoacetamido)phenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1415)

Isolated as a white solid (0.110 g, 98%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)furan-2-carboxamide(F1416)

Isolated as a white solid (0.089 g, 76%).

2-Chloro-N-(3-(2-cyclopropylacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1417)

Isolated as a white solid (0.104 g, 91%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(3,3,3-trifluoropropanamido)phenyl)benzamide(F1418)

Isolated as a white solid (0.103 g, 87%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(3-ethoxypropanamido)-2,4-difluorophenyl)benzamide(F1419)

Isolated as a white foam (0.098 g, 84%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,3,3,4,4,4-heptafluorobutanamido)phenyl)benzamide(F1463)

Isolated as a white foam (0.087 g, 65%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoro-2-phenylacetamido)-2,4-difluorophenyl)benzamide(F1471)

Isolated as a light yellow foam (0.086 g, 68%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-propionamidophenyl)benzamide(F1472)

Isolated as a white solid (0.074 g, 67%).

N-(3-Butyramido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1473)

Isolated as a white solid (0.088 g, 79%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-pentanamidophenyl)benzamide(F1474)

Isolated as a white solid (0.092 g, 80%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(3-oxocyclobutane-1-carboxamido)phenyl)benzamide(F1475)

Isolated as a white foam (0.106 g, 91%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,3,3-tetrafluoropropanamido)phenyl)benzamide(F1534)

Isolated as a white solid (0.037 g, 65%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,3,3-tetrafluoropropanamido)phenyl)benzamide(F1535)

Isolated as a white solid (0.039 g, 67%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,3,3-tetrafluoropropanamido)phenyl)benzamide(F1564)

Isolated as a white solid (0.104 g, 76%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,3,3-tetrafluoropropanamido)phenyl)benzamide(F1565)

Isolated as a white solid (0.043 g, 58%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,3,3-tetrafluoropropanamido)phenyl)benzamide(F1567)

Isolated as a white solid (0.107 g, 87%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,3,3-tetrafluoropropanamido)phenyl)benzamide(F1568)

Isolated as a white solid (0.096 g, 78%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,3,3-tetrafluoropropanamido)phenyl)benzamide(F1569)

Isolated as a white solid (0.099 g, 80%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2-ethoxypropanamido)-2,4-difluorophenyl)benzamide(F1604)

Isolated as a white solid (0.093 g, 79%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2-ethoxy-2-methylpropanamido)-2,4-difluorophenyl)benzamide(F1605)

Isolated as a white foam (0.097 g, 81%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-isobutyramidophenyl)benzamide(F1606)

Isolated as a white solid (0.084 g, 75%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(3,3,3-trifluoro-2-(trifluoromethyl)propanamido)phenyl)benzamide(F1607)

Isolated as a white solid (0.115 g, 88%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluorocyclopropane-1-carboxamido)-2,4-difluorophenyl)benzamide(F1608)

Isolated as a white solid (0.102 g, 87%).

2-Chloro-N-(3-(1-cyanocyclopropane-1-carboxamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1609)

Isolated as a white foam (0.090 g, 77%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)tetrahydrofuran-3-carboxamide(F1610)

Isolated as a white foam (0.111 g, 95%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)tetrahydrofuran-2-carboxamide(F1611)

Isolated as a white foam (0.066 g, 56%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2-ethoxy-N-methylpropanamido)-2,4-difluorophenyl)benzamide(F1616)

Isolated as a white foam (0.093 g, 79%).

2-Chloro-N-(3-(2-cyano-N-methylacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1617)

Isolated as a white foam (0.096 g, 86%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-methoxy-N-methylacetamido)phenyl)benzamide(F1630)

Isolated as a white foam (0.082 g, 92%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2-ethoxypropanamido)-2,4-difluorophenyl)benzamide(F1645)

Isolated as a white solid (0.079 g, 68%). The title compound wasprepared fromN-(3-amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)benzamide which was prepared via methodsdescribed in U.S. Patent Application Publication US20160304522A1 (F315).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-methoxyacetamido)phenyl)benzamide(F1646)

Isolated as a white solid (0.087 g, 78%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)tetrahydrofuran-2-carboxamide(F1647)

Isolated as a white foam (0.071 g, 77%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)furan-2-carboxamide(F1648)

Isolated as a white foam (0.072 g, 62%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(3-oxocyclobutane-1-carboxamido)phenyl)benzamide(F1649)

Isolated as a white foam (0.040 g, 35%).

2-Chloro-N-(3-(2-cyanoacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1650)

Isolated as a yellow foam (0.062 g, 56%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(3,3,3-trifluoropropanamido)phenyl)benzamide(F1651)

Isolated as a white foam (0.074 g, 63%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,3,3,4,4,4-heptafluorobutanamido)phenyl)benzamide(F1652)

Isolated as a white foam (0.052 g, 39%).

2-Chloro-N-(3-(2-cyclopropylacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1653)

Isolated as a white foam (0.099 g, 88%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-propionamidophenyl)benzamide(F1654)

Isolated as a white foam (0.099 g, 90%).

N-(3-Butyramido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1655)

Isolated as a white foam (0.095 g, 85%).

N-(3-Butyramido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-chloro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1659)

Isolated as a white foam (0.067 g, 75%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-chloro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2-ethoxypropanamido)-2,4-difluorophenyl)benzamide(F1660)

Isolated as a white solid (0.071 g, 77%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-chloro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)tetrahydrofuran-2-carboxamide(F1661)

Isolated as a white solid (0.069 g, 75%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(1-(trifluoromethyl)cyclopropane-1-carboxamido)phenyl)benzamide(F1662)

Isolated as a white foam (0.033, 27%).

(R)—N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)pyrrolidine-2-carboxamide(F1663)

Isolated as a white foam (0.044 g, 38%).

(S)—N-(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)pyrrolidine-2-carboxamide(F1664)

Isolated as a white foam (0.039 g, 33%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)isoxazole-5-carboxamide(F1671)

Isolated as a white foam (0.069 g, 70%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)isothiazole-5-carboxamide(F1672)

Isolated as a white foam (0.059 g, 58%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-phenylacetamido)phenyl)benzamide(F1673)

Isolated as a white foam (0.073 g, 72%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-dichloroacetamido)-2,4-difluorophenyl)benzamide(F1685)

Isolated as a white foam (0.104 g, 88%).

2-Chloro-N-(3-(2-chloro-2,2-difluoroacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1686)

Isolated as a white foam (0.097 g, 82%).

2-Chloro-N-(3-(2-chloro-2,2-difluoroacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1697)

Isolated as a white foam (0.104 g, 87%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(3-(2-ethoxypropanamido)-2,4-difluorophenyl)benzamide(F1698)

Isolated as a white solid (0.098 g, 83%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)tetrahydrofuran-2-carboxamide(F1699)

Isolated as a white foam (0.107 g, 91%).

2-Chloro-N-(3-(2-cyanoacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1700)

Isolated as a white foam (0.089 g, 80%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(3,3,3-trifluoropropanamido)phenyl)benzamide(F1701)

Isolated as a white foam (0.098 g, 82%).

2-Chloro-N-(3-(2-cyclopropylacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1702)

Isolated as a white solid (0.094 g, 82%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,3,3-tetrafluoropropanamido)phenyl)benzamide(F1703)

Isolated as a white foam (0.110 g, 89%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-propionamidophenyl)benzamide(F1704)

Isolated as a white foam (0.103 g, 94%).

N-(3-Butyramido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1705)

Isolated as a white solid (0.99 g, 88%).

2-Chloro-N-(3-(2-chloro-2,2-difluoroacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-chloro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1719)

Isolated as a white foam (0.54 g, 76%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-((S)-2-ethoxypropanamido)-2,4-difluorophenyl)benzamide(F1731)

Isolated as a white foam (0.080 g, 69%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-((R)-2-ethoxypropanamido)-2,4-difluorophenyl)benzamide(F1732)

Isolated as a white foam (0.097 g, 83%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-((S)-2-ethoxypropanamido)-2,4-difluorophenyl)benzamide(F1733)

Isolated as a white foam (0.068 g, 58%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-((R)-2-ethoxypropanamido)-2,4-difluorophenyl)benzamide(F1734)

Isolated as a white foam (0.081 g, 69%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,3,3,4,4,4-heptafluorobutanamido)phenyl)benzamide(F1741)

Isolated as a white solid (0.051 g, 38%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(trifluoromethoxy)acetamido)phenyl)benzamide(F1742)

Isolated as a white solid (0.104 g, 86%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-oxopropanamido)phenyl)benzamide(F1754)

Isolated as a white solid (0.035 g, 40%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(4,4,4-trifluoro-3-methylbutanamido)phenyl)benzamide(F1760)

Isolated as a white foam (0.101 g, 82%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(trifluoromethoxy)acetamido)phenyl)benzamide(F1766)

Isolated as a white foam (0.100 g, 82%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(trifluoromethoxy)propanamido)phenyl)benzamide(F1767)

Isolated as a white foam (0.096 g, 78%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(trifluoromethoxy)acetamido)phenyl)benzamide(F1768)

Isolated as a white foam (0.101 g, 83%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(trifluoromethoxy)propanamido)phenyl)benzamide(F1769)

Isolated as a white foam (0.109 g, 87%).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2-(trifluoromethoxy)acetamido)phenyl)-2,3-difluorobenzamide(F1777)

Isolated as a white foam (0.058 g, 83%).

N-(3-(5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzamido)-2,4-difluorophenyl)tetrahydrofuran-2-carboxamide(F1778)

Isolated as a white foam (0.046 g, 68%).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,3,3,4,4,4-heptafluorobutanamido)phenyl)-2,3-difluorobenzamide(F1779)

Isolated as a white foam (0.053 g, 70%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(trifluoromethoxy)acetamido)phenyl)-N-methylbenzamide(F1793)

Isolated as a white foam (0.107 g, 88%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2-ethoxypropanamido)-2,4-difluorophenyl)-N-methylbenzamide(F1794)

Isolated as a white foam (0.088 g, 75%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(trifluoromethoxy)acetamido)phenyl)-N-methylbenzamide(F1796)

Isolated as a white foam (0.095 g, 79%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2-ethoxypropanamido)-2,4-difluorophenyl)-N-methylbenzamide(F1797)

Isolated as a white foam (0.092 g, 79%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-methylbenzamido)-2,6-difluorophenyl)tetrahydrofuran-2-carboxamide(F1798)

Isolated as a white foam (0.098 g, 84%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(4,4,4-trifluorobutanamido)phenyl)benzamide(F1800)

Isolated as a white foam (0.11 g, 92%).

trans-5-(3-(3,5-bis(Trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluoro-3-(2-(trifluoromethoxy)acetamido)phenyl)benzamide(F1804)

Isolated as a white foam (0.106 g, 89%).

trans-N-(3-(5-(3-(3,5-bis(Trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamido)-2,6-difluorophenyl)tetrahydrofuran-2-carboxamide(F1805)

Isolated as a white foam (0.105 g, 91%).

trans-5-(3-(3,5-bis(Trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-N-(3-butyramido-2,4-difluorophenyl)-2-chlorobenzamide(F1806)

Isolated as a white foam (0.098 g, 89%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)isoxazole-5-carboxamide(F1816)

Isolated as a white foam (0.078 g, 84%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)isothiazole-5-carboxamide(F1817)

Isolated as a white foam (0.036 g, 38%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)isoxazole-3-carboxamide(F1818)

Isolated as a white foam (0.067 g, 72%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)-1-(2,2,2-trifluoroethyl)-1H-pyrazole-3-carboxamide(F1819)

Isolated as a white foam (0.070 g, 67%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)-1,2,3-thiadiazole-5-carboxamide(F1820)

Isolated as a white foam (0.040 g, 42%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)-3-(trifluoromethyl)isoxazole-5-carboxamide(F1824)

Isolated as a white foam (0.024 g, 24%).

trans-5-(3-(3,5-bis(Trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluoro-3-(2,2,3,3,4,4,4-heptafluorobutanamido)phenyl)benzamide(F1825)

Isolated as a white foam (0.105 g, 80%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(4,4,4-trifluoro-3-(trifluoromethyl)butanamido)phenyl)benzamide(F1833)

Isolated as a white foam (0.114 g, 86%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(4,4-difluoropentanamido)-2,4-difluorophenyl)benzamide(F1843)

Isolated as a white foam (0.100 g, 84%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(4,4,5,5,5-pentafluoropentanamido)phenyl)benzamide(F1844)

Isolated as a white foam (0.113 g, 88%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(3-methylbutanamido)phenyl)benzamide(F1845)

Isolated as a white foam (0.101 g, 88%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(2,2,2-trifluoroethoxy)acetamido)phenyl)benzamide(F1846)

Isolated as a white foam (0.119 g, 80%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(4,4,4-trifluorobutanamido)phenyl)benzamide(F1847)

Isolated as a white foam (0.105 g, 86%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(4,4,4-trifluorobutanamido)phenyl)benzamide(F1848)

Isolated as a white foam (0.101 g, 83%).

N-(3-(1-Acetylcyclopropane-1-carboxamido)-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1850)

Isolated as a white solid (0.044 g, 42%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(4,4-difluoropentanamido)-2,4-difluorophenyl)benzamide(F1860)

Isolated as a white solid (0.103 g, 85%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(4,4,5,5,5-pentafluoropentanamido)phenyl)benzamide(F1861)

Isolated as a white foam (0.119 g, 92%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(4,4,4-trifluoro-2-methylbutanamido)phenyl)benzamide(F1862)

Isolated as a white foam (0.047 g, 38%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(2,2,2-trifluoroethoxy)acetamido)phenyl)benzamide(F1863)

Isolated as a white foam (0.109 g, 88%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(3-(4,4-difluoropentanamido)-2,4-difluorophenyl)benzamide(F1864)

Isolated as a white foam (0.100 g, 83%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(4,4,5,5,5-pentafluoropentanamido)phenyl)benzamide(F1865)

Isolated as a white foam (0.113 g, 86%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(4,4,4-trifluoro-2-methylbutanamido)phenyl)benzamide(F1866)

Isolated as a white foam (0.094 g, 75%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(2,2,2-trifluoroethoxy)acetamido)phenyl)benzamide(F1867)

Isolated as a white foam (0.115 g, 92%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-fluoroacrylamido)phenyl)benzamide(F1871)

Isolated as a white foam (0.047 mg, 42%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-fluoroacrylamido)phenyl)benzamide(F1872)

Isolated as an off-white foam (0.053 g, 47%).

N-(3-(But-3-enamido)-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1873)

Isolated as a white foam (0.065 g, 69%).

N-(3-(But-3-enamido)-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1874)

Isolated as a white foam (0.097 g, 87%).

N-(3-(But-3-enamido)-2,6-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzamide(F1875)

Isolated as a white foam (0.054 g, 84%).

N-(3-(But-3-enamido)-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1876)

Isolated as a white foam (0.074 g, 66%).

N-(3-Acrylamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1877)

Isolated as a white solid (0.041 g, 21%).

The following compounds were prepared in like manner to the procedureoutlined in Example 5:

N-(3-Acetamido-2,4-dichlorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1412)

Isolated as a white solid (0.043 g, 29%).

N-(3-Acetamido-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzamide(F1433)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy oil (0.086 g, 76%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,4-difluorophenyl)carbamate(F1434)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a white solid (0.330 g, 88%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,4-difluorophenyl)carbamate(F1435)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a white solid (0.270 g, 76%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,4-difluorophenyl)carbamate(F1436)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a white foam (0.320 g, 81%).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-2,3-difluorobenzamide(F1437)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a brown powder (0.050 g, 38%).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-2,3-difluorobenzamide(F1438)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.058 g, 48%).

N-(3-Acetamido-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzamide(F1439)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy oil (0.024 g, 21%).

5-((1R,3R)-2,2-Dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-2,3-difluorobenzamide(F1440)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated s a glassy oil (0.040 g, 32%).

5-((1R,3R)-2,2-Dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-2,3-difluorobenzamide(F1441)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy oil (0.028 g, 22%).

N-(3-Acetamido-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzamide(F1442)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a pale solid (0.100 g, 84%).

5-((1R,3R)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-2,3-difluorobenzamide(F1443)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy oil (0.085 g, 67%).

5-((1R,3R)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-2,3-difluorobenzamide(F1444)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.058 g, 45%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamido)-2,4-difluorophenyl)carbamate(F1445)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a foamy solid (0.325 g, 98%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(N-ethyl-2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1452)

Isolated as a white foam (0.148 g, 94%).

tert-Butyl-N-((tert-butoxy)carbonyl)-N-[3-[[5-[[(1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropanecarbonyl]amino]-2-fluoro-benzoyl]amino]-2,6-difluoro-phenyl]carbamate(F1453)

Isolated as a colorless oil (0.661 g, 76%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoro-N-methylacetamido)-2,4-difluorophenyl)benzamide(F1460)

Isolated as a white foam (0.117 g, 78%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoro-N-methylacetamido)-2,4-difluorophenyl)benzamide(F1461)

Isolated as a white foam (0.119 g, 82%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoro-N-methylacetamido)-2,4-difluorophenyl)benzamide(F1462)

Isolated as a white foam (0.111 g, 75%).

N-(3-(N-Allyl-2,2-difluoroacetamido)-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1482)

Isolated as a clear, colorless oil (0.052 g, 33%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(N-methylacetamido)phenyl)benzamide(F1506)

Isolated as a white foam (0.057 g, 39%).

5-((1R,3R)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)-2-fluorobenzamide(F1512)

Isolated as a white solid (0.068 g, 46%).

5-((1R,3R)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-2-fluorobenzamide(F1513)

Isolated as a white solid (0.064 g, 42%).

N-(3-Acetamido-2,6-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-2-fluorobenzamide(F1514)

Isolated as a white foam (0.031 g, 24%).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-2-fluorobenzamide(F1526)

Isolated as a white solid (0.083 g, 56%).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-2-fluorobenzamide(F1527)

Isolated as a white solid (0.065 g, 46%).

N-(3-Acetamido-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-2-fluorobenzamide(F1528)

Isolated as a brown solid (0.088 g, 65%).

5-((1R,3R)-2,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-2-fluorobenzamide(F1529)

Isolated as a white solid (0.100 g, 67%).

5-((1R,3R)-2,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-2-fluorobenzamide(F1530)

Isolated as a white solid (0.095 g, 66%).

N-(3-acetamido-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-2-fluorobenzamide(F1531)

Isolated as a brown solid (0.117 g, 85%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)(methyl)carbamate(F1549)

Isolated as a colorless glass (1.05 g, 98%).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)-2-fluorobenzamide(F1551)

Isolated as a yellow foam (0.087 g, 59%).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)-2-fluorobenzamide(F1552)

Isolated as a yellow foam (0.073 g, 51%).

N-(5-Acetamido-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-2-fluorobenzamide(F1553)

Isolated as a white foam (0.081 g, 60%).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-2-fluorobenzamide(F1554)

Isolated as a white foam (0.092 g, 63%).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)-2-fluorobenzamide(F1555)

Isolated as a white foam (0.073 g, 51%).

N-(3-Acetamido-2,6-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-2-fluorobenzamide(F1556)

Isolated as a white solid (0.083 g, 61%).

5-((1R,3R)-2,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)-2-fluorobenzamide(F1557)

Isolated as a white foam (0.114 g, 76%).

5-((1R,3R)-2,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)-2-fluorobenzamide(F1558)

Isolated as a yellow foam (0.112 g, 77%).

N-(5-Acetamido-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-2-fluorobenzamide(F1559)

Isolated as a white foam (0.122 g, 89%).

5-((1R,3R)-2,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-2-fluorobenzamide(F1560)

Isolated as a white foam (0.128 g, 86%).

5-((1R,3R)-2,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)-2-fluorobenzamide(F1561)

Isolated as a white foam (0.101 g, 70%).

N-(3-Acetamido-2,6-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-2-fluorobenzamide(F1562)

Isolated as a white solid (0.108 g, 79%).

N-(3-Acetamido-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzamide(F1570)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.046 g, 61%).

5-((1R,3R)-2,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-2,3-difluorobenzamide(F1571)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy white solid (0.054 g, 68%).

5-((1R,3R)-2,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-2,3-difluorobenzamide(F1572)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.057 g, 70%).

5-((1R,3R)-2,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)-2,3-difluorobenzamide(F1573)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.024 g, 29%).

5-((1R,3R)-2,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-2,3-difluorobenzamide(F1574)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.060 g, 73%).

N-(3-Acetamido-2,6-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzamide(F1575)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.062 g, 91%).

N-(3-Acetamido-2,6-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzamide(F1576)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.055 g, 73%).

5-((1R,3R)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)-2,3-difluorobenzamide(F¹⁵⁷⁷)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.058 g, 72%).

5-((1R,3R)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-2,3-difluorobenzamide(F1578)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.048 g, 65%).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)-2,3-difluorobenzamide(F1579)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.055 g, 68%).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)-2,3-difluorobenzamide(F1580)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.061 g, 82%).

N-(5-Acetamido-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzamide(F1581)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.055 g, 70%).

5-((1R,3R)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)-2,3-difluorobenzamide(F1582)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.053 g, 68%).

5-((1R,3R)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)-2,3-difluorobenzamide(F1583)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.052 g, 61%).

5-((1R,3R)-2,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)-2,3-difluorobenzamide(F1584)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.057 g, 74%).

N-(5-Acetamido-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzamide(F1585)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a brown glassy solid (0.060 g, 79%).

5-((1R,3R)-2,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)-2,3-difluorobenzamide(F1586)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.054 g, 72%).

N-(5-Acetamido-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzamide(F1587)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.055 g, 69%).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)-2,3-difluorobenzamide(F1588)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated s a glassy solid (0.060 g, 83%).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,6-difluorophenyl)-2,3-difluorobenzamide(F1589)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.046 g, 58%).

N-(3-Acetamido-2,6-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzamide(F1590)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a glassy solid (0.066 g, 98%).

N-(3-Acetamido-2,4,6-trifluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1613)

Isolated as a white solid (0.076 g, 52%).

N-(3-Acetamido-2,4,6-trifluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1627)

Isolated as a white solid (0.083 g, 55%).

N-(3-Acetamido-2,4,6-trifluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1628)

Isolated as a white solid (0.081 g, 55%).

N-(3-Acetamido-2,4,6-trifluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1629)

Isolated as a white solid (0.095 g, 64%).

trans-N-(2-Acetamido-3,5-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1632)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a waxy solid (0.038 g, 50%).

trans-N-(2-Acetamido-4,6-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1633)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a pale waxy solid (0.035 g, 46%).

trans-N-(2-Acetamido-4,5-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1634)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a pale solid (0.061 g, 80%).

trans-N-(5-Acetamido-2-fluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1635)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a pale waxy solid (0.042 g, 54%).

trans-N-(2-Acetamido-6-fluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1636)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a waxy pale solid (0.041 g, 55%).

trans-N-(2-Acetamido-4-fluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1637)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a pale semi solid (0.020 g, 24%).

trans-N-(3-Acetamido-4-fluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1638)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a pale solid (0.007 g, 10%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-fluoro-5-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1639)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a pale solid (0.011 g, 13%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-fluoro-5-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1640)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a pale solid (0.020 g, 23%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-fluoro-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1641)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a pale solid (0.015 g, 21%).

tert-ButylN-tert-butoxycarbonyl-N-[5-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropanecarbonyl]amino]benzoyl]amino]-2,4-difluoro-3-methyl-phenyl]carbamate(F1670)

Isolated as a white solid (0.240 g, 88%).

tert-ButylN-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-[3-fluoro-5-(trifluoromethyl)phenyl]cyclopropanecarbonyl]amino]benzoyl]amino]-2,6-difluoro-phenyl]carbamate(F1681)

Isolated as a white foam (1.14 g, 86%).

N-(4-Bromo-2-methyl-3-nitrophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1688)

Isolated as a yellow foam (0.140 g, 92%).

tert-Butyl(5-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,3,4-trifluorophenyl)carbamate(F1736)

Isolated as a white foam (0.288 g, 90%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-iodophenyl)benzamide(F1758)

Isolated as a white foam (0.338 g, 71%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)(ethyl)carbamate(F1761)

Isolated as a white foam (0.540 g, 54%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-fluoro-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1812)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a foamy solid (0.140 g, 92%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-fluoro-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1813)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a pale solid (0.142 g, 93%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(4-fluoro-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1814)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a pale solid (0.133 g, 90%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(4-fluoro-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1815)

The title compound was synthesized with a reaction time of 24-48 hoursand isolated as a pale solid (0.136 g, 87%).

The following compounds were prepared in like manner to the procedureoutlined in Example 6:

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-dichloropropanamido)-2,4-difluorophenyl)benzamide(F1351)

Isolated as a white solid (0.062 g, 49%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoropropanamido)-2,4-difluorophenyl)benzamide(F1352)

Isolated as a white solid (0.134 g, 74%).

N-(3-(2-Bromo-2-methylpropanamido)-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1354)

Isolated as a white solid (0.038 g, 29%).

2-Chloro-N-(3-(2,2-dibromoacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1355)

Isolated as a white solid (0.111 g, 79%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluorobutanamido)-2,4-difluorophenyl)benzamide(F1357)

Isolated as a white solid (0.165 g, 89%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(1-methylcyclopropane-1-carboxamido)phenyl)benzamide(F1362)

Isolated as a white solid (0.107 g, 89%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2-ethoxyacetamido)-2,4-difluorophenyl)benzamide(F1363)

Isolated as a white foam (0.106 g, 88%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2-ethoxypropanamido)-2,4-difluorophenyl)benzamide(F1364)

Isolated as a white solid (0.101 g, 82%).

2-Chloro-N-(3-(2-cyanoacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1369)

Isolated as a yellow foam (0.112 g, 96%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-propionamidophenyl)benzamide(F1371)

Isolated as a white solid (0.180 g, 78%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-pentanamidophenyl)benzamide(F1372)

Isolated as a white foam (0.191 g, 80%).

N-(3-Butyramido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1385)

Isolated as a white solid (0.103 g, 88%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,3,3,4,4,4-heptafluorobutanamido)phenyl)benzamide(F1450)

Isolated as a white foam (0.119 g, 85%).

N-(3-Acetamido-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1454)

Isolated as a white foam (0.168 g, 65%).

N-(3-(2-Bromopropanamido)-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1479)

Isolated as a white solid (0.120 g, 93%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)tetrahydrofuran-3-carboxamide(F1480)

Isolated as a white foam (0.104 g, 85%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,3,3-tetrafluorocyclobutane-1-carboxamido)phenyl)benzamide(F1481)

Isolated as a white foam (0.114 g, 86%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-isobutyramidophenyl)benzamide(F1483)

Isolated as a white solid (0.108 g, 92%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(3-oxocyclopentane-1-carboxamido)phenyl)benzamide(F1488)

Isolated as a gold foam (0.113 g, 91%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(3-methoxypropanamido)phenyl)benzamide(F1489)

Isolated as a white foam (0.094 g, 78%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)oxetane-2-carboxamide(F1503)

Isolated as a white solid (0.036 g, 30%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-dimethyl-3-oxocyclobutane-1-carboxamido)-2,4-difluorophenyl)benzamide(F1507)

Isolated as a white solid (0.090 g, 71%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)tetrahydrofuran-2-carboxamide(F1521)

Isolated as a white foam (0.054 g, 44%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2-ethoxy-2-methylpropanamido)-2,4-difluorophenyl)benzamide(F1603)

Isolated as a clear, colorless oil (0.047 g, 38%).

(2S,5S)—N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)-5-methyltetrahydrofuran-2-carboxamide(F1612)

Isolated as a white foam (0.100 g, 80%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)-5-oxotetrahydrofuran-2-carboxamide(F1625)

Isolated as a white solid (0.110 g, 88%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)-5-ethyltetrahydrofuran-2-carboxamide(F1626)

Isolated as a clear colorless oil (0.105 g, 82%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-methylbutanamido)phenyl)benzamide(F1642)

Isolated as a white solid (0.092 g, 77%).

2-Chloro-N-(3-(cyclopentanecarboxamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1643)

Isolated as a white solid (0.086 g, 70%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(3,3-difluorocyclobutane-1-carboxamido)-2,4-difluorophenyl)benzamide(F1644)

Isolated as a white solid (0.100 g, 79%).

2-Chloro-N-(3-(2-chloropropanamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1667)

Isolated as a white solid (0.112 g, 92%).

2-Chloro-N-(3-(2-chlorobutanamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1668)

Isolated as a white solid (0.097 g, 78%).

2-Chloro-N-(3-(3-chlorobutanamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1669)

Isolated as a white solid (0.097 g, 78%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)tetrahydrofuran-2-carboxamide(F1676)

Isolated as a white solid (0.076 g, 82%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,3,3-tetrafluoropropanamido)phenyl)benzamide(F1677)

Isolated as a clear colorless oil (0.061 g, 63%).

N-(3-Acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1678)

Isolated as a white solid (0.069 g, 81%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-propionamidophenyl)benzamide(F1679)

Isolated as a white solid (0.070 g, 81%).

2-Chloro-N-(3-(2-cyclopropylacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1682)

Isolated as a white foam (0.113 g, 94%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(3,3,3-trifluoropropanamido)phenyl)benzamide(F1683)

Isolated as a white foam (0.114 g, 91%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-((R)-2-methoxypropanamido)phenyl)benzamide(F1689)

Isolated as a white foam (0.082 g, 68%).

(R)—N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)tetrahydrofuran-2-carboxamide(F1691)

Isolated as a white foam (0.103 g, 84%).

(S)—N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)tetrahydrofuran-2-carboxamide(F1692)

Isolated as a white foam (0.088 g, 72%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)tetrahydrofuran-2-carboxamide(F1706)

Isolated as a white solid (0.060 g, 65%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,3,3-tetrafluoropropanamido)phenyl)benzamide(F1707)

Isolated as a clear, colorless oil (0.066 g, 69%).

N-(3-Acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1708)

Isolated as a white solid (0.057 g, 67%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-propionamidophenyl)benzamide(F1709)

Isolated as a white solid (0.063 g, 73%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(3,3,3-trifluoropropanamido)phenyl)benzamide(F1710)

Isolated as a white solid (0.068 g, 73%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-methoxypropanamido)phenyl)benzamide(F1712)

Isolated as a white solid (0.110 g, 91%).

N-(3-(5-((1R,3R)-3-(3-Bromo-4-fluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamido)-2,6-difluorophenyl)tetrahydrofuran-2-carboxamide(F1714)

Isolated as a white solid (0.036 g, 59%).

5-((1R,3R)-3-(3-Bromo-4-fluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluoro-3-(2,2,3,3-tetrafluoropropanamido)phenyl)benzamide(F1715)

Isolated as a white solid (0.030 g, 47%).

N-(3-Acetamido-2,4-difluorophenyl)-5-((1R,3R)-3-(3-bromo-4-fluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamide(F1716)

Isolated as a white solid (0.037 g, 66%).

5-((1R,3R)-3-(3-Bromo-4-fluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluoro-3-propionamidophenyl)benzamide(F1717)

Isolated as a white solid (0.042 g, 73%).

5-((1R,3R)-3-(3-Bromo-4-fluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluoro-3-(3,3,3-trifluoropropanamido)phenyl)benzamide(F1718)

Isolated as a white solid (0.031 g, 50%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-((S)-2-methoxypropanamido)phenyl)benzamide(F1720)

Isolated as a white solid (0.101 g, 84%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)tetrahydrothiophene-2-carboxamide(F1721)

Isolated as a white solid (0.110 g, 88%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)tetrahydro-2H-pyran-3-carboxamide(F1722)

Isolated as a white solid (0.102 g, 82%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-methoxyacetamido)phenyl)benzamide(F1724)

Isolated as a white solid (0.098 g, 83%).

2-Chloro-N-(3-(2-chloroacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1726)

Isolated as a white foam (0.090 g, 76%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,3-dichloropropanamido)-2,4-difluorophenyl)benzamide(F1728)

Isolated as a white foam (0.060 g, 47%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(3-fluoropropanamido)phenyl)benzamide(F1735)

Isolated as a white solid (0.100 g, 85%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2-ethoxypropanamido)-2,4-difluorophenyl)benzamide(F1737)

Isolated as a white solid (0.077 g, 83%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(3,3,3-trifluoropropanamido)phenyl)benzamide(F1738)

Isolated as a white solid (0.078 g, 83%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-propoxypropanamido)phenyl)benzamide(F1739)

Isolated as a white solid (0.101 g, 81%).

N-(5-Acetamido-2,3,4-trifluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1743)

Isolated as a white foam (0.078 g, 92%).

2-Chloro-N-(3-(2-(cyclopropylmethoxy)propanamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1745)

Isolated as a white solid (0.081 g, 85%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-isobutoxypropanamido)phenyl)benzamide(F1746)

Isolated as a white foam (0.067 g, 70%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(2,2,2-trifluoroethoxy)propanamido)phenyl)benzamide(F1747)

Isolated as a white foam (0.081 g, 82%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)-3-methyloxirane-2-carboxamide(F1748)

Isolated as a white solid (0.028 g, 31%).

2-Chloro-N-(3-(2-cyano-N-methylacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1752)

Isolated as a white foam (0.062 g, 72%).

2-Chloro-N-(3-(2-cyanopropanamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1755)

Isolated as a white solid (0.067 g, 75%).

2-Chloro-N-(3-(2-cyanobutanamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1756)

Isolated as a white solid (0.033 g, 36%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2-ethoxybutanamido)-2,4-difluorophenyl)benzamide(F1757)

Isolated as a white solid (0.026 g, 28%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2-ethoxypentanamido)-2,4-difluorophenyl)benzamide(F1759)

Isolated as a white solid (0.096 g, 75%).

2-Chloro-N-(3-(2-cyano-N-ethylacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1763)

Isolated as a white foam (0.071 g, 81%).

2-Chloro-N-(3-(2-cyano-N-ethylpropanamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1764)

Isolated as a white foam (0.061 g, 68%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(trifluoromethoxy)propanamido)phenyl)benzamide(F1771)

Isolated as a tan foam (0.080 g, 82%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(trifluoromethoxy)acetamido)phenyl)benzamide(F1772)

Isolated as a white foam (0.032 g, 36%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(trifluoromethoxy)propanamido)phenyl)benzamide(F1773)

Isolated as a white foam (0.043 g, 47%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(trifluoromethoxy)acetamido)phenyl)benzamide(F1774)

Isolated as a tan foam (0.071 g, 79%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(trifluoromethoxy)propanamido)phenyl)benzamide(F1775)

Isolated as a white solid (0.073 g, 80%).

5-((1R,3R)-3-(3-Bromo-4-fluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluoro-3-(2-(trifluoromethoxy)acetamido)phenyl)benzamide(F1780)

Isolated as a white solid (0.070 g, 79%).

5-((1R,3R)-3-(3-Bromo-4-fluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(2,4-difluoro-3-(2-(trifluoromethoxy)propanamido)phenyl)benzamide(F1781)

Isolated as a white solid (0.074 g, 82%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)-2,3,3,4,4,5,5-heptafluorotetrahydrofuran-2-carboxamide(F1782)

Isolated as a white solid (0.079 g, 73%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)-2,3,3,4,4,5,5,6,6-nonafluorotetrahydro-2H-pyran-2-carboxamide(F1783)

Isolated as a white solid (0.033 g, 29%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(N-ethyl-2-(trifluoromethoxy)acetamido)-2,4-difluorophenyl)benzamide(F1789)

Isolated as a white solid (0.058 g, 61%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2-(difluoromethoxy)acetamido)-2,4-difluorophenyl)benzamide(F1790)

Isolated as a white foam (0.078 g, 84%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(perfluoroethoxy)acetamido)phenyl)benzamide(F1808)

Isolated as a white solid (0.078 g, 76%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)-2-methyltetrahydrofuran-2-carboxamide(F1809)

Isolated as a white solid (0.061 g, 65%).

2-Chloro-N-(3-(2-cyano-N-(prop-2-yn-1-yl)acetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1810)

Isolated as a white foam (0.144 g, 99%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(N-(prop-2-yn-1-yl)-2-(trifluoromethoxy)acetamido)phenyl)benzamide(F1811)

Isolated as a clear, colorless oil (0.027 g, 20%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(1-((trifluoromethoxy)methyl)cyclopropane-1-carboxamido)phenyl)benzamide(F1821)

Isolated as a white solid (0.024 g, 24%).

Ethyl3-((3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)amino)-2-fluoro-3-oxopropanoate(F1822)

Isolated as a white foam (0.097 g, 100%).

2-Chloro-N-(3-(2-cyano-N-(2-fluoroethyl)acetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1823)

Isolated as a white foam (0.053 g, 68%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2-ethoxy-N-ethylpropanamido)-2,4-difluorophenyl)benzamide(F1827)

Isolated as a gold oil (0.065 g, 71%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2-(difluoromethoxy)propanamido)-2,4-difluorophenyl)benzamide(F1828)

Isolated as a white foam (0.037 g, 39%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(4,5,5,5-tetrafluoro-4-(trifluoromethyl)pentanamido)phenyl)benzamide(F1829)

Isolated as a white foam (0.081 g, 75%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(5,5,5-trifluoropentanamido)phenyl)benzamide(F1830)

Isolated as a white solid (0.070 g, 72%).

N-(3-(2-Bromo-4,4,4-trifluorobutanamido)-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1831)

Isolated as a white foam (0.073 g, 69%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(3,3,3-trifluoro-2-methylpropanamido)phenyl)benzamide(F1832)

Isolated as a white foam (0.032 g, 34%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,3,3-tetrafluoro-3-(trifluoromethoxy)propanamido)phenyl)benzamide(F1834)

Isolated as a clear colorless oil (0.014 g, 13%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(4,4,4-trifluoro-2-methylbutanamido)phenyl)benzamide(F1835)

Isolated as a white solid (0.044 g, 45%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-(1-(trifluoromethyl)cyclopropyl)acetamido)phenyl)benzamide(F1836)

Isolated as a white solid (0.060 g, 61%).

N-(3-(2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)-2-(trifluoromethyl)tetrahydrofuran-3-carboxamide(F1837)

Isolated as a white solid (0.042 g, 42%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,3,4,4,4-hexafluorobutanamido)phenyl)benzamide(F1839)

Isolated as a white solid (0.043 g, 42%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(4,4,4-trifluoro-3-oxobutanamido)phenyl)benzamide(F1840)

Isolated as a gold solid (0.029 g, 30%).

2-Chloro-N-(3-(2-cyano-N-propylacetamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1841)

Isolated as a white solid (0.096 g, 64%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2-ethoxy-N-propylpropanamido)-2,4-difluorophenyl)benzamide(F1842)

Isolated as a white solid (0.056 g, 29%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(1-(trifluoromethyl)cyclobutane-1-carboxamido)phenyl)benzamide(F1849)

Isolated as a white solid (0.006 g, 6%).

N-(3-(3-Bromopropanamido)-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1851)

Isolated as a white solid (0.043 g, 44%).

N-(3-(3-Bromobutanamido)-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1853)

Isolated as a white solid (0.054 g, 55%).

2-Chloro-N-(3-(3-cyclopropylpropanamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1854)

Isolated as a white solid (0.061 g, 67%).

2-Chloro-N-(3-(3-cyanopropanamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1855)

Isolated as a white solid (0.007 g, 8%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(5,5-dimethylhexanamido)-2,4-difluorophenyl)benzamide(F1856)

Isolated as a white solid (0.074 g, 77%).

2-Chloro-N-(3-(4-cyanobutanamido)-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1857)

Isolated as a white solid (0.060 g, 66%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(4,5,5,5-tetrafluoro-4-(trifluoromethoxy)pentanamido)phenyl)benzamide(F1858)

Isolated as a white solid (0.082 g, 74%).

N-(3-((E)-But-2-enamido)-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1868)

Isolated as a white solid (0.055 g, 47%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-((E)-4,4,4-trifluorobut-2-enamido)phenyl)benzamide(F1869)

Isolated as a white solid (0.096 g, 76%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2-fluoroacrylamido)phenyl)benzamide(F1870)

Isolated as a white solid (0.064 g, 54%).

N-(3-(But-3-enamido)-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1878)

Isolated as a white solid (0.076 g, 86%).

N-(3-(But-3-enamido)-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1879)

Isolated as a white solid (0.076 g, 86%).

5-((1R,3R)-3-(3-Bromo-4-fluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-N-(3-(but-3-enamido)-2,4-difluorophenyl)-2-chlorobenzamide(F1880)

Isolated as a white solid (0.089 g, 100%).

The following compounds were prepared in like manner to the procedureoutlined in Example 7:

Methyl2-((3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)amino)-2-oxoacetate(F1753)

Isolated as a white solid (0.064 g, 72%).

The following compounds were prepared in like manner to the procedureoutlined in Example 9:

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-((3,3,3-trifluoropropyl)sulfonamido)phenyl)benzamide(F1350)

Isolated as a clear colorless oil (0.019 g, 14%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(((2,2-dichlorocyclopropyl)methyl)sulfonamido)-2,4-difluorophenyl)benzamide(F1361)

Isolated as a white foam (0.028 g, 20%).

The following compounds were prepared in like manner to the procedureoutlined in Example 10:

trans-tert-Butyl(4-(((4-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-3-methylphenyl)amino)methyl)phenyl)carbamate(F1348)

Isolated as a yellow oil (0.109 g, 76%).

The following compounds were prepared in like manner to the procedureoutlined in Example 12:

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-((4-hydroxybenzyl)amino)-2-methylphenyl)benzamide(F1353)

Isolated as a pale yellow foam (0.057 g, 69%).

The following compounds were prepared in like manner to the procedureoutlined in Example 13:

N-(3-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1337)

Isolated as a white solid (0.166 g, 80%).

N-(3-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1338)

Isolated as an off-white powder (0.154 g, 73%).

N-(3-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1339)

Isolated as a light yellow solid (0.153 g, 74%).

trans-N-(4-((4-Aminobenzyl)amino)-2-methylphenyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1349)

Isolated as a yellow solid (0.018 g, 26%).

trans-N-(3-Amino-4-chlorophenyl)-2-chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1365)

Isolated as a white solid (0.143 g, 84%).

trans-N-(4-Amino-3,5-dichlorophenyl)-2-chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1367)

Isolated as a tan solid (0.154 g, 61%).

trans-N-(4-Amino-3-chlorophenyl)-2-chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1370)

Isolated as a white foam (0.170 g, 70%).

trans-N-(4-Amino-3-cyanophenyl)-2-chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1387)

Isolated as a white foam (0.106 g, 34%).

N-(4-Amino-2,3-dimethylphenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1389)

Isolated as a white solid (0.111 g, 64%).

trans-N-(4-Amino-3-(trifluoromethyl)phenyl)-2-chloro-5-(2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1390)

Isolated as a white foam (0.191 g, 67%).

N-(3-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1391)

Isolated as a tan solid (0.600 g, 98%).

N-(5-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1395)

Isolated as a light-tan solid (0.276 g, 83%).

N-(5-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1396)

Isolated as a tan solid (0.319 g, 95%).

N-(5-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1397)

Isolated as a light-tan solid (0.302 g, 92%).

N-(5-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1398)

Isolated as a tan solid (0.311 g, 92%).

N-(5-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1399)

Isolated as a light-tan solid (0.301 g, 95%).

N-(3-Amino-4-methylphenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1413)

Isolated as a white solid (0.143 g, 65%).

N-(3-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1426)

Isolated as a white powder (0.176 g, 76%).

N-(3-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1427)

Isolated as an off-white solid (0.194 g, 82%).

N-(3-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1428)

Isolated as a tan powder (0.163 g, 70%).

N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1446)

Isolated as an off-white solid (0.167 g, 66%).

N-(3-Amino-2-methylphenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1448)

Isolated as a white solid (0.146 g, 80%).

N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1449)

Isolated as an off-white solid (0.193 g, 78%).

N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1458)

Isolated as an off-white powder (0.154 g, 64%).

N-(3-Amino-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-2-fluorobenzamide(F1459)

Isolated as a light yellow foam (0.382 g, 80%).

N-(5-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1470)

Isolated as an off-white powder (0.194 g, 85%).

N-(5-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1477)

Isolated as an off-white powder (0.155 g, 61%).

N-(5-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1478)

Isolated as an off-white powder (0.185 g, 70%).

N-(5-Amino-2,4-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-2-fluorobenzamide(F1490)

Isolated as a light brown foam (0.387 g, 89%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(methylamino)phenyl)benzamide(F1550)

Isolated as a yellow foam (0.870 g, 97%).

N-(5-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1566)

Isolated as a tan solid (0.210 g, 89%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(4-fluoro-3-iodophenyl)cyclopropane-1-carboxamido)benzamide(F1622)

Isolated as a tan foam (0.108 g, 94%).

N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-chloro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1631)

Isolated as a tan solid (0.64 g, 98%).

N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1666)

Isolated as a white solid (0.860 g, 85%).

N-(5-Amino-2,4-difluoro-3-methylphenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1674)

Isolated as a white solid (0.151 g, 79%).

N-(3-Amino-6-bromo-2-methylphenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1684)

Isolated as a white solid (0.039 g, 75%).

N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1687)

Isolated as a white solid (0.784 g, 87%).

N-(3-Amino-2,4-difluorophenyl)-5-((1R,3R)-3-(3-bromo-4-fluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamide(F1713)

Isolated as a white solid (0.308 g, 85%).

N-(5-Amino-2,3,4-trifluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1740)

Isolated as a white foam (0.188 g, 91%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(ethylamino)-2,4-difluorophenyl)benzamide(F1762)

Isolated as a white foam (0.424 g, 87%).

N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-methylbenzamide(F1785)

Isolated as a brown foam (0.565 g, 98%).

trans-N-(3-Amino-2,4-difluorophenyl)-5-(3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamide(F1791)

Isolated as a white foam (1.27 g, 98%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(prop-2-yn-1-ylamino)phenyl)benzamide(F1807)

Isolated as an amber oil (0.215 g, 72%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-((2-fluoroethyl)amino)phenyl)benzamide(F1826)

Isolated as a gold oil (0.147 g, 68%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(propylamino)phenyl)benzamide(F1838)

Isolated as a clear, colorless oil (0.331 g, 66%).

The following compounds were prepared in like manner to the procedureoutlined in Example 14:

N-(3-Amino-2,6-difluorophenyl)-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzamide(F1770)

Isolated as a white foam (0.274 g, 81%).

The following compounds were prepared in like manner to the procedureoutlined in Example 15:

N-(3-Amino-4-bromo-2-methylphenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1690)

Isolated as a white foam (0.090 g, 69%).

The following compounds were prepared in like manner to the procedureoutlined in Example 18:

5-((1R,3R)-3-(3-Bromo-4-fluorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1410)

Isolated as a white solid (0.059 g, 35%).

5-((1R,3R)-3-(3-Bromo-4-chlorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1411)

Isolated as a white solid (0.053 g, 32%).

The following compounds were prepared in like manner to the procedureoutlined in Example 20:

tert-ButylN-tert-butoxycarbonyl-N-[5-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-(3-chloro-4-fluoro-phenyl)cyclopropanecarbonyl]amino]-3-fluoro-benzoyl]amino]-2,4-difluoro-phenyl]carbamate(F1379)

Isolated as a white solid (0.429 g, 79%).

tert-ButylN-tert-butoxycarbonyl-N-[5-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropanecarbonyl]amino]-3-fluoro-benzoyl]amino]-2,4-difluoro-phenyl]carbamate(F1380)

Isolated as a white solid (0.402 g, 69%).

tert-ButylN-tert-butoxycarbonyl-N-[5-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropanecarbonyl]amino]-3-fluoro-benzoyl]amino]-2,4-difluoro-phenyl]carbamate(F1381)

Isolated as a white solid (0.425 g, 70%).

tert-ButylN-tert-butoxycarbonyl-N-[5-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropanecarbonyl]amino]-3-fluoro-benzoyl]amino]-2,4-difluoro-phenyl]carbamate(F1382)

Isolated as a white solid (0.355 g, 62%).

tert-ButylN-tert-butoxycarbonyl-N-[5-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarbonyl]amino]-3-fluoro-benzoyl]amino]-2,4-difluoro-phenyl]carbamate(F1383)

Isolated as a white solid (0.266 g, 47%).

3-((1R,3R)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1447)

Isolated as a white foam (0.123 g, 56%).

trans-5-(3-(3-Bromo-5-chlorophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chloro-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1618)

Isolated as a white foam (0.077 g, 76%). The title compound was preparedfromtrans-3-(3-bromo-5-chlorophenyl)-2,2-dichlorocyclopropane-1-carboxylicacid which was prepared via methods described in U.S. Patent ApplicationPublication US20160304522A1 (C215).

trans-tert-ButylN-[3-[[5-[[3-(3-bromo-4,5-dichlorophenyl)-2,2-dichlorocyclopropanecarbonyl]amino]-2-chlorobenzoyl]amino]-2,6-difluorophenyl]-N-tert-butoxycarbonyl-carbamate(F1619)

Isolated as a white solid (0.139 g, 88%).

trans-tert-ButylN-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[2,2-dichloro-3-(4-fluoro-3-iodophenyl)cyclopropanecarbonyl]amino]benzoyl]amino]-2,6-difluorophenyl]carbamate(F1620)

Isolated as a white solid (0.155 g, 97%).

tert-ButylN-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-[4-chloro-3-(trifluoromethyl)phenyl]cyclopropanecarbonyl]amino]benzoyl]amino]-2,6-difluoro-phenyl]carbamate(F1621)

Isolated as a colorless glass (0.87 g, 99%).

tert-ButylN-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-[3-(trifluoromethyl)phenyl]cyclopropanecarbonyl]amino]benzoyl]amino]-2,6-difluoro-phenyl]carbamate(F1665)

Isolated as a white foam (1.35 g, 91%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trifluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1693)

Isolated as an off-white solid (0.500 g, 35%).2-Chloro-5-((1S,3S)-2,2-dichloro-3-(3,4,5-trifluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1749)

Isolated as an off-white solid (0.360 g, 46%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-difluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1750)

Isolated as an off-white solid (0.500 g, 50%).

2-Chloro-5-((1S,3S)-2,2-dichloro-3-(3,4-difluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)benzamide(F1751)

Isolated as a pale yellow solid (0.500 g, 50%).

tert-ButylN-[3-[[5-[[(1R,3R)-3-(3-bromo-4-fluoro-phenyl)-2,2-dichloro-cyclopropanecarbonyl]amino]-2-chloro-benzoyl]amino]-2,6-difluoro-phenyl]-N-tert-butoxycarbonyl-carbamate(F1776)

Isolated as a white solid (1.2 g, 93%).

tert-ButylN-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropanecarbonyl]amino]benzoyl]-methyl-amino]-2,6-difluoro-phenyl)carbamate(F1784)

Isolated as a white foam (0.730 g, 82%).

trans-tert-ButylN-[3-[[5-[[3-[3,5-bis(trifluoromethyl)phenyl]-2,2-dichloro-cyclopropanecarbonyl]amino]-2-chloro-benzoyl]amino]-2,6-difluoro-phenyl]-N-tert-butoxycarbonyl-carbamate(F1786)

Isolated as a white foam (1.7 g, 92%). The title compound was preparedfromtrans-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropanecarboxylicacid which was prepared via methods described in U.S. Patent ApplicationPublication US20160304522A1 (C₈).

trans-tert-ButylN-[3-[[5-[[3-[3-bromo-5-(trifluoromethyl)phenyl]-2,2-dichloro-cyclopropanecarbonyl]amino]-2-chloro-benzoyl]amino]-2,6-difluoro-phenyl]-N-tert-butoxycarbonyl-carbamate(F1787)

Isolated as a white foam (1.7 g, 94%).

tert-ButylN-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropanecarbonyl]amino]benzoyl]amino]-2,6-difluoro-phenyl]carbamate(F1788)

Isolated as a white foam (1.9 g, 94%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-(2,2,2-trifluoroacetamido)ethyl)benzamide(F2066)

Isolated as a white solid (0.075 g, 24%).

trans-N-(3-Acetamidopropyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F2067)

Isolated as a white solid (0.100 g, 34%).

trans-N-(4-Acetamidobutyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F2068)

Isolated as a white solid (0.140 g, 47%).

trans-N-(5-Acetamidopentyl)-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F2069)

Isolated as a white solid (0.100 g, 33%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(methylamino)-3-oxopropyl)benzamide(F2070)

Isolated as a white solid (0.090 g, 32%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,2-difluoropropyl)benzamide(F2075)

Isolated as an off-white solid (0.150 g, 60%).

trans-Ethyl3-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,2-difluoropropanoate(F2076)

Isolated as a pale yellow solid (0.120 g, 46%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,2-difluoro-2-phenylethyl)benzamide(F2077)

Isolated as an off-white solid (0.150 g, 57%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)benzamide(F2078)

Isolated as an off-white solid (0.063 g, 19%).

trans-2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-oxo-3-(2,2,2-trifluoroethylamino)propyl)benzamide(F2079)

Isolated as an off-white solid (0.140 g, 39%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-oxo-4-(2,2,2-trifluoroethylamino)butyl)benzamide(F2080)

Isolated as an off-white solid (0.089 g, 26%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-oxo-2-(3,3,3-trifluoropropylamino)ethyl)benzamide(F2081)

Isolated as an off-white solid (0.075 g, 19%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-(2,2,2-trifluoroacetamido)ethyl)benzamide(F2082)

Isolated as an off-white solid (0.060 g, 32%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,2-difluorobutyl)benzamide(F2086)

Isolated as an off-white solid (0.050 g, 28%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,2-difluoropropyl)benzamide(F2087)

Isolated as an off-white solid (0.100 g, 60%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,2-difluorobutyl)-3-fluorobenzamide(F2088)

Isolated as an off-white solid (0.150 g, 30%).

trans-Ethyl3-(2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamido)-2,2-difluoropropanoate(F2089)

Isolated as an off-white solid (0.100 g, 21%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-3-fluoro-N-(2-oxopropyl)benzamide(F2090)

Isolated as an off-white solid (0.100 g, 18%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,2-difluoro-2-phenylethyl)-3-fluorobenzamide(F2091)

Isolated as an off-white solid (0.090 g, 13%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-oxo-3-(3,3,3-trifluoropropylamino)propyl)benzamide(F2092)

Isolated as an off-white solid (0.125 g, 31%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropanecarboxamido)-N-(4-oxo-4-(3,3,3-trifluoropropylamino)butyl)benzamide(F2093)

Isolated as a pale pink solid (0.130 g, 31%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2,2-trifluoroacetamido)propyl)benzamide(F2094)

Isolated as an off-white solid (0.075 g, 19%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-(2,2,2-trifluoroacetamido)butyl)benzamide(F2095)

Isolated as an off-white solid (0.171 g, 42%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2-(2,2,3,3,3-pentafluoropropanamido)ethyl)benzamide(F2096)

Isolated as an off-white solid (0.170 g, 40%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3-(2,2,3,3,3-pentafluoropropanamido)propyl)benzamide(F2097)

Isolated as a pale blue solid (0.131 g, 30%).

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(4-(2,2,3,3,3-pentafluoropropanamido)butyl)benzamide(F2098)

Isolated as an off-white solid (0.151 g, 34%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-difluorophenyl)cyclopropane-1-carboxamido)-N-(2,2,2-trifluoroethyl)benzamide(F2099)

Isolated as an off-white solid (0.450 g, 48%). The title compound wasprepared from 5-amino-2-chloro-N-(2,2,2-trifluoroethyl)benzamide, whichwas prepared using methods described in U.S. Patent ApplicationPublication 20160302418A1 (C70).

2-Chloro-5-((1S,3S)-2,2-dichloro-3-(3,4-difluorophenyl)cyclopropane-1-carboxamido)-N-(2,2,2-trifluoroethyl)benzamide(F2100)

Isolated as an off-white solid (0.450 g, 48%). The title compound wasprepared from 5-amino-2-chloro-N-(2,2,2-trifluoroethyl)benzamide, whichwas prepared using methods described in U.S. Patent ApplicationPublication 20160302418A1 (C70).

The following compounds were prepared in like manner to the procedureoutlined in Example 21:

trans-N-(3-Amino-2,4-difluorophenyl)-5-(3-(4-bromophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamide(F1591)

Isolated as a white foam (0.108 g, 36%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(4-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1592)

Isolated as a white foam (0.092 g, 27%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(4-chlorophenyl)cyclopropane-1-carboxamido)benzamide(F1593)

Isolated as a white foam (0.162 g, 50%).

trans-N-(3-Amino-2,4-difluorophenyl)-5-(3-(3-bromophenyl)-2,2-dichlorocyclopropane-1-carboxamido)-2-chlorobenzamide(F1594)

Isolated as a white foam (0.103 g, 34%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3-chlorophenyl)cyclopropane-1-carboxamido)benzamide(F1595)

Isolated as a white foam (0.152 g, 47%).

trans-N-(3-Amino-2,4-difluorophenyl)-2-chloro-5-(2,2-dichloro-3-(3-fluorophenyl)cyclopropane-1-carboxamido)benzamide(F1596)

Isolated as a white foam (0.199 g, 59%).

The following compounds were prepared in like manner to the procedureoutlined in Example 22:

trans-2-Chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(3,5-dichloro-4-hydroxyphenyl)benzamide(F1360)

Isolated as a tan foam (0.096 g, 93%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-3-methylbenzamido)-2,4-difluorophenyl)carbamate(F1420)

Isolated as a tan foam (0.270 g, 91%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-3-methylbenzamido)-2,4-difluorophenyl)carbamate(F1421)

Isolated as an off-white solid (0.274 g, 94%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-3-methylbenzamido)-2,4-difluorophenyl)carbamate(F1422)

Isolated as an off-white solid (0.271 g, 100%).

tert-ButylN-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropanecarbonyl]amino]-3-methyl-benzoyl]amino]-2,6-difluoro-phenyl]carbamate(F1423)

Isolated as an off-white solid (0.320 g, 100%).

tert-ButylN-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropanecarbonyl]amino]-3-methyl-benzoyl]amino]-2,6-difluoro-phenyl]carbamate(F1424)

Isolated as an off-white solid (0.325 g, 98%).

tert-ButylN-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropanecarbonyl]amino]-3-methyl-benzoyl]amino]-2,6-difluoro-phenyl]carbamate(F1425)

Isolated as an off-white solid (0.315 g, 100%).

tert-ButylN-tert-butoxycarbonyl-N-[5-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropanecarbonyl]amino]-3-methyl-benzoyl]amino]-2,4-difluoro-phenyl]carbamate(F1455)

Isolated as an off-white solid (0.305 g, 100%)

tert-ButylN-tert-butoxycarbonyl-N-[5-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropanecarbonyl]amino]-3-methyl-benzoyl]amino]-2,4-difluoro-phenyl]carbamate(F1456)

Isolated as an off-white solid (0.335 g, 100%)

tert-ButylN-tert-butoxycarbonyl-N-[5-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropanecarbonyl]amino]-3-methyl-benzoyl]amino]-2,4-difluoro-phenyl]carbamate(F1457)

Isolated as an off-white solid (0.352 g, 100%).

The following compounds were prepared in like manner to the procedureoutlined in Example 25:

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoro-N-methylacetamido)-2,4-difluorophenyl)benzamide(F1386)

Isolated as a white foam (0.122 g, 79%).

tert-Butyl-N-((tert-butoxy)carbonyl)-N-[5-[[5-[[(1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropanecarbonyl]amino]-2-fluoro-benzoyl]amino]-2,4-difluoro-phenyl]carbamate(F1467)

Isolated as a white solid (0.590 g, 68%).

N-(3-Acetamido-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1515)

Isolated as a white solid (0.100 g, 73%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1516)

Isolated as a white solid (0.118 g, 79%).

N-(5-Acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1517)

Isolated as a white solid (0.116 g, 85%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1518)

Isolated as a tan solid (0.114 g, 79%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1519)

Isolated as a white solid (0.118 g, 79%).

N-(3-Acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1532)

Isolated as a white solid (0.119 g, 87%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1533)

Isolated as a white solid (0.121 g, 79%).

N-(3-Acetamido-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamide(F1536)

Isolated as a white solid (0.131 g, 90%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1537)

Isolated as a white solid (0.141 g, 91%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1538)

Isolated as a white solid (0.138 g, 90%).

N-(5-Acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamide(F1539)

Isolated as a white solid (0.127 g, 90%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(5-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide(F1540)

Isolated as a tan solid (0.137 g, 94%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluoro-5-(2,2,2-trifluoroacetamido)phenyl)benzamide(F1541)

Isolated as a white solid (0.133 g, 89%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,4-difluorophenyl)carbamate(F1542)

Isolated as a white solid (0.712 g, 93%).

tert-ButylN-tert-butoxycarbonyl-N-[5-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropanecarbonyl]amino]benzoyl]amino]-2,4-difluoro-phenyl]carbamate(F1563)

Isolated as a white solid (0.310 g, 90%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-4-fluoro-N-phenylbenzamide(F1723)

Isolated as a light-tan solid (0.070 g, 79%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-4-fluoro-N-(4-fluorophenyl)benzamide(F1725)

Isolated as a light-tan solid (0.091 g, 97%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-4-fluorobenzamide(F1727)

Isolated as a white solid (0.085 g, 88%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)-4-fluorobenzamide(F1729)

Isolated as a white solid (0.093 g, 83%).

tert-ButylN-tert-butoxycarbonyl-N-[3-[[2-chloro-5-[[(1R,3R)-2,2-dichloro-3-[4-fluoro-3-(trifluoromethyl)phenyl]cyclopropanecarbonyl]amino]-4-fluoro-benzoyl]amino]-2,6-difluoro-phenyl]carbamate(F1730)

Isolated as a white solid (0.102 g, 79%).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-N-(2,6-difluoro-3-nitrophenyl)-2,3-difluorobenzamide(F1765)

Isolated as a white foam (0.425 g, 44%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)(prop-2-yn-1-yl)carbamate(F1881)

Isolated as a yellow oil (0.33 g, 80%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)(2-fluoroethyl)carbamate(F1882)

Isolated as an amber oil (0.24 g, 63%).

tert-Butyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)(propyl)carbamate(F1883)

Isolated as a white foam (0.55 g, 65%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-N-ethyl-4-fluorobenzamide(F2083)

Isolated as a white solid (0.051 g, 63%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-4-fluoro-N-(2,2,2-trifluoroethyl)benzamide(F2084)

Isolated as a white solid (0.070 g, 78%).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-4-fluoro-N-(2,2,3,3,3-pentafluoropropyl)benzamide(F2085)

Isolated as a white solid (0.078 g, 80%).

The following compounds were prepared in like manner to the procedureoutlined in Example 32:

Ethyl(3-(2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)benzamido)-2,6-difluorophenyl)carbamate(F1476)

Isolated as a tan foam (0.034 g, 30%).

The following compounds were prepared in like manner to the procedureoutlined in Example 39:

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-3-methylbenzoicacid (C224)

Isolated as a white solid (0.60 g, 77%): mp 212-215° C.; ¹H NMR (400MHz, Acetone-d₆) δ 11.30 (br s, 1H), 10.09 (s, 1H), 8.07 (d, J=2.7 Hz,1H), 7.83 (d, J=2.7 Hz, 1H), 7.68 (d, J=1.9 Hz, 1H), 7.63 (d, J=8.3 Hz,1H), 7.45 (dd, J=8.3, 1.7 Hz, 1H), 3.63 (d, J=8.3 Hz, 1H), 3.38 (d,J=8.3 Hz, 1H), 2.42 (s, 3H); ¹³C NMR (101 MHz, Acetone-d₆) δ 166.20,162.50, 138.25, 137.21, 134.35, 132.38, 131.88, 131.48, 130.99, 130.54,129.20, 126.66, 123.79, 119.06, 62.01, 39.28, 37.38, 19.94; ESIMS m/z468 ([M+H]⁺).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-3-methylbenzoicacid (C225)

Isolated as a white solid (0.635 g, 85%): mp 195-200° C.; ¹H NMR (400MHz, Acetone-d₆) δ 10.09 (s, 1H), 8.06 (d, J=2.6 Hz, 1H), 7.83 (d, J=2.5Hz, 1H), 7.71 (d, J=0.8 Hz, 2H), 3.66 (d, J=8.3 Hz, 1H), 3.45 (d, J=8.3Hz, 1H), 2.42 (s, 3H); ¹³C NMR (101 MHz, Acetone-d₆) δ 166.18, 162.30,138.26, 137.18, 134.90, 133.64, 132.39, 130.22, 129.76, 126.70, 123.79,119.07, 61.79, 39.34, 37.08, 19.94; ESIMS m/z 501 ([M+H]⁺).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-3-methylbenzoicacid (C226)

Isolated as a white solid (0.570 g, 75%): mp 190-193° C.; ¹H NMR (400MHz, Acetone-d₆) δ 11.39 (br s, 1H), 10.08 (s, 1H), 8.07 (d, J=2.6 Hz,1H), 7.87-7.81 (m, 3H), 7.48 (t, J=9.9 Hz, 1H), 3.71 (d, J=8.3 Hz, 1H),3.43 (d, J=8.3 Hz, 1H), 2.42 (s, 3H); ¹⁹F NMR (376 MHz, Acetone-d₆) δ−61.87 (d, J=12.8 Hz), −117.65 (q, J=12.8 Hz); ESIMS m/z 484 ([M+H]⁺).

5-((1R,3R)-2,2-Dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-2-fluorobenzoicacid (C227)

Isolated as a grey foam (1.6 g, 93%): ¹H NMR (400 MHz, DMSO-d₆) δ 13.32(s, 1H), 10.86 (s, 1H), 8.21 (dd, J=6.6, 2.8 Hz, 1H), 7.85 (ddd, J=9.0,4.1, 2.8 Hz, 1H), 7.75 (d, J=2.1 Hz, 1H), 7.69 (d, J=8.3 Hz, 1H), 7.42(dd, J=8.4, 2.2 Hz, 1H), 7.31 (dd, J=10.5, 8.9 Hz, 1H), 3.59 (d, J=8.5Hz, 1H), 3.43 (d, J=8.5 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −116.06;ESIMS m/z 438 ([M+H]⁺).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-2-fluorobenzoicacid (C228)

Isolated as a brown foam (1.15 g, 80%): ¹H NMR (400 MHz, DMSO-d₆) δ13.34 (s, 1H), 10.83 (s, 1H), 8.21 (dd, J=6.6, 2.8 Hz, 1H), 7.85 (ddd,J=9.0, 4.2, 2.9 Hz, 1H), 7.80 (s, 2H), 7.32 (dd, J=10.5, 8.9 Hz, 1H),3.62 (d, J=8.5 Hz, 1H), 3.51 (d, J=8.5 Hz, 1H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −116.06; ESIMS m/z 472 ([M+H]⁺).

5-((1R,3R)-2,2-Dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-2-fluorobenzoicacid (C229)

Isolated as a cream solid (1.01 g, 88%): ¹H NMR (400 MHz, DMSO-d₆) δ13.34 (s, 1H), 10.86 (s, 1H), 8.22 (dd, J=6.6, 2.9 Hz, 1H), 7.90-7.78(m, 3H), 7.59 (dd, J=10.7, 8.6 Hz, 1H), 7.32 (dd, J=10.5, 8.9 Hz, 1H),3.68 (d, J=8.4 Hz, 1H), 3.47 (d, J=8.5 Hz, 1H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −59.92 (d, J=12.9 Hz), −116.06, −116.98 (q, J=13.0 Hz); ESIMSm/z 454 ([M+H]⁺).

5-((1R,3R)-2,2-Dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-2,3-difluorobenzoicacid (C230)

Isolated as a brown foam (0.73 g, 88%): ¹H NMR (400 MHz, DMSO-d₆) δ13.69 (s, 1H), 11.02 (s, 1H), 8.00 (ddd, J=12.2, 6.6, 2.7 Hz, 1H), 7.93(dt, J=4.7, 2.0 Hz, 1H), 7.81 (d, J=0.7 Hz, 2H), 3.66-3.61 (m, 1H), 3.53(d, J=8.5 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −135.50 (d, J=22.7 Hz),−142.58 (d, J=22.6 Hz); ESIMS m/z 488 ([M+H]⁺).

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)-cyclopropane-1-carboxamido)-4-fluorobenzoicacid (C231)

Isolated as a cream-colored solid (1.23 g, 68%): mp 188-191° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 13.54 (s, 1H), 10.73 (s, 1H), 8.60 (d, J=8.4 Hz,1H), 7.82 (ddd, J=11.1, 6.0, 2.4 Hz, 2H), 7.68 (d, J=10.7 Hz, 1H), 7.60(dd, J=10.7, 8.5 Hz, 1H), 3.73 (d, J=8.5 Hz, 1H), 3.68 (d, J=8.6 Hz,1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −59.94 (d, J=12.4 Hz), −116.92 (q,J=12.4 Hz), −118.01; HRMS-ESI (m/z) [M+]⁺ calcd for C₁₈H₉Cl₃F₅NO₃,486.9568; found, 486.9579.

2-Chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)-cyclopropane-1-carboxamido)benzoicacid (C232)

Isolated as a tan solid (5.8 g, 93%): ¹H NMR (400 MHz, DMSO-d₆) δ 13.48(s, 1H), 10.94 (s, 1H), 8.17 (d, J=2.7 Hz, 1H), 7.94-7.72 (m, 3H),7.68-7.44 (m, 2H), 3.68 (d, J=8.4 Hz, 1H), 3.49 (d, J=8.5 Hz, 1H); ¹⁹FNMR (376 MHz, DMSO-d₆) δ −59.93 (d, J=12.6 Hz), −116.95 (q, J=12.5 Hz);ESIMS m/z 472 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 40:

trans-2,2-Dichloro-3-(3-fluorophenyl)cyclopropane-1-carboxylic acid(C233)

Isolated as a pale yellow solid (2.8 g, 52%): ¹H NMR (400 MHz, DMSO-d₆)δ 13.39 (s, 1H), 5 7.46-7.39 (m, 1H), 7.29 (t, J=8.0 Hz, 2H), 7.21-7.15(m, 1H), 3.45 (d, J=8.0 Hz, 1H), 3.41 (d, J=8.8 Hz, 1H); ESIMS m/z247.11 ([M−H]⁻).

trans-2,2-Dichloro-3-(3-chlorophenyl)cyclopropane-1-carboxylic acid(C234)

Isolated as a white solid (1.1 g, 23%): ¹H NMR (400 MHz, DMSO-d₆) δ13.39 (s, 1H), 7.52 (s, 1H), 7.42-7.38 (m, 3H), 3.45 (d, J=8.4 Hz, 1H),3.41 (d, J=8.4 Hz, 1H); ESIMS m/z 262.73 ([M−H]⁻).

trans-3-(3-Bromophenyl)-2,2-dichlorocyclopropane-1-carboxylic acid(C235)

Isolated as a white solid (1.25 g, 26%): ¹H NMR (400 MHz, DMSO-d₆) δ13.41 (s, 1H), 7.66 (s, 1H), 7.54 (d, J=7.6 Hz, 1H), 7.43 (d, J=7.6 Hz,1H), 7.34 (t, J=8.0 Hz, 1H), 3.45 (d, J=8.8 Hz, 1H), 3.42 (d, J=8.4 Hz,1H); ESIMS m/z 307.05 ([M−H]⁻)

trans-2,2-Dichloro-3-(3-(trifluoromethoxy)phenyl)cyclopropane-1-carboxylicacid (C236

Isolated as a pale yellow solid (1.8 g, 38%): ¹H NMR (400 MHz, DMSO-d₆)δ 13.39 (s, 1H), 7.54-7.43 (m, 3H), 7.34 (d, J=8.0 Hz, 1H), 3.51 (d,J=8.8 Hz, 1H), 3.44 (d, J=8.8 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−56.76; ESIMS m/z 312.77 ([M−H]⁻).

trans-2,2-Dichloro-3-(4-fluorophenyl)cyclopropane-1-carboxylic acid(C237)

Isolated as a white solid (2.5 g, 43%): ¹H NMR (400 MHz, DMSO-d₆) δ13.39 (s, 1H), 7.46-7.42 (m, 2H), 7.23-7.17 (m, 2H), 3.41 (d, J=8.4 Hz,1H), 3.30 (d, J=8.4 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −114.31; ESIMSm/z 246.78 ([M−H]⁻).

trans-2,2-Dichloro-3-(4-chlorophenyl)cyclopropane-1-carboxylic acid(C238)

Isolated as a pale yellow solid (2.4 g, 44%): ¹H NMR (400 MHz, DMSO-d₆)δ 13.29 (s, 1H), 7.48-7.42 (m, 4H), 3.43 (d, J=8.8 Hz, 1H), 3.33 (d,J=8.8 Hz, 1H); ESIMS m/z 262.73 ([M−H]⁻).

trans-3-(4-Bromophenyl)-2,2-dichlorocyclopropane-1-carboxylic acid(C239)

Isolated as a white solid (0.45 g, 9%): ¹H NMR (400 MHz, DMSO-d₆) δ 7.56(d, J=8.8 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 3.38 (d, J=8.4 Hz, 1H), 3.28(d, J=8.4 Hz, 1H); ESIMS m/z 306.72 ([M−H]⁻).

The following compounds were prepared in like manner to the procedureoutlined in Example 51:

trans-2,2-Dichloro-3-(4-fluoro-3-iodophenyl)cyclopropane-1-carboxylicacid (C240)

Isolated as a white solid (1.35 g, 80%): mp 147-149° C.; ¹H NMR (400MHz, CDCl₃) δ 7.67-7.62 (m, 1H), 7.62 (dd, J=6.4, 2.4 Hz, 1H), 6.93-6.88(m, 1H), 3.45 (d, J=4.4 Hz, 1H), 2.88 (d, J=4.4 Hz, 1H); ESIMS m/z374.98 ([M+H]⁺).

trans-2,2-Dichloro-3-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (C241)

Isolated as a white solid (24 g, 43%): ¹H NMR (400 MHz, CDCl₃) δ 9.55(s, 1H), 7.66-7.59 (m, 1H), 7.57-7.44 (m, 3H), 3.55 (d, J=8.3 Hz, 1H),2.94 (d, J=8.3 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −62.70; ESIMS m/z 298([M−H]⁻).

The following compounds were prepared in like manner to the procedureoutlined in Example 55:

(1R,3R)-3-(3-Bromo-4-chlorophenyl)-2,2-dichlorocyclopropane-1-carboxylicacid (C242)

Isolated as a white solid (1.05 g, 42%, 93% ee): ¹H NMR (400 MHz, CDCl₃)δ 7.53 (d, J=2.1 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.17 (dd, J=8.4, 2.1Hz, 1H), 3.43 (d, J=8.2 Hz, 1H), 2.86 (d, J=8.3 Hz, 1H); ESIMS m/z 343([M−H]⁻). Racemictrans-3-(3-bromo-4-chlorophenyl)-2,2-dichlorocyclopropane-1-carboxylicacid can be prepared via methods described in U.S. Patent ApplicationPublication US20160304522A1 (C422). The title compound was obtained fromthe racemate using (S)-1-phenylethan-1-amine and example 55 conditions.

The following compounds were prepared in like manner to the procedureoutlined in Example 57:

tert-ButylN-[5-[(5-amino-2-chloro-3-fluoro-benzoyl)amino]-2,4-difluoro-phenyl]-N-tert-butoxycarbonyl-carbamate(C245)

Isolated as a light-orange solid (3.125 g, 79%): 143-152° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 10.38 (s, 1H), 7.69 (t, J=8.1 Hz, 1H), 7.52 (t,J=10.1 Hz, 1H), 6.59 (ddd, J=7.7, 5.5, 2.5 Hz, 2H), 5.81 (s, 2H), 1.40(s, 18H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −115.57, −117.36, −117.38,−121.88, −121.90; HRMS-ESI (m/z) [M+]⁺ calcd for C₂₃H₂₅ClF₃N₃O₅,515.1435; found, 515.1438.

The following compounds were prepared in like manner to the procedureoutlined in Example 61:

N-(2,6-Difluoro-3-nitrophenyl)-N-ethyl-2,2-difluoroacetamide (C246)

Isolated as a gold oil (0.45 g, 25%): ¹H NMR (400 MHz, CDCl₃) δ8.39-8.15 (m, 1H), 7.21 (dddd, J=11.9, 9.7, 7.9, 2.0 Hz, 1H), 6.08 (dt,J=154.5, 53.3 Hz, 1H), 4.01-3.69 (m, 2H), 1.21 (tt, J=7.3, 1.2 Hz, 3H);ESIMS m/z 280 ([M+H]⁺).

N-Allyl-N-(2,6-difluoro-3-nitrophenyl)-2,2-difluoroacetamide (C247)

Isolated as a gold oil (0.21 g, 12%): ¹H NMR (300 MHz, CDCl₃) δ 8.23(dddd, J=15.3, 9.5, 8.1, 5.5 Hz, 1H), 7.35-7.09 (m, 1H), 6.54-5.71 (m,2H), 5.30-5.09 (m, 2H), 4.52-4.25 (m, 2H); ESIMS m/z 293 ([M+H]⁺).

N-(2,6-Difluoro-3-nitrophenyl)-N-methylacetamide (C248)

Isolated as a tan solid (1.02 g, 61%): ¹H NMR (400 MHz, CDCl₃) δ 8.15(dddd, J=31.6, 9.4, 8.1, 5.5 Hz, 1H), 7.32-7.05 (m, 1H), 3.31 (d, J=53.3Hz, 3H), 2.13 (d, J=164.4 Hz, 3H); ESIMS m/z 231 ([M+H]⁺).

tert-Butyl (2,6-difluoro-3-nitrophenyl)(ethyl)carbamate (C249)

Isolated as a yellow oil (0.4 g, 69%): ¹H NMR (400 MHz, CDCl₃) δ8.21-8.00 (m, 1H), 7.10 (ddd, J=9.8, 8.2, 2.0 Hz, 1H), 3.62 (dq, J=25.2,7.3 Hz, 2H), 1.37 (s, 9H), 1.15 (dt, J=17.2, 7.2 Hz, 3H); ESIMS m/z 303([M+H]⁺).

tert-Butyl (2,6-difluoro-3-nitrophenyl)(prop-2-yn-1-yl)carbamate (C250)

Isolated as a yellow oil (0.40 g, 67%): ¹H NMR (400 MHz, CDCl₃) δ8.20-8.03 (m, 1H), 7.12 (ddd, J=9.7, 8.2, 2.0 Hz, 1H), 4.53-4.28 (m,2H), 2.21 (dt, J=20.9, 2.6 Hz, 1H), 1.56 (d, J=3.4 Hz, 9H); ESIMS m/z313 ([M+H]⁺).

tert-Butyl (2,6-difluoro-3-nitrophenyl)(2-fluoroethyl)carbamate (C251)

Isolated as a yellow oil (0.198 g, 32%): ¹H NMR (400 MHz, CDCl₃) δ8.19-7.99 (m, 1H), 7.21-7.01 (m, 1H), 4.76-4.45 (m, 2H), 4.07-3.77 (m,2H), 1.39 (s, 9H); ESIMS m/z 321 ([M+H]⁺).

tert-Butyl (2,6-difluoro-3-nitrophenyl)(propyl)carbamate (C252)

Isolated as a yellow oil (0.350 g, 58%): ¹H NMR (400 MHz, CDCl₃) δ 8.09(m, 1H), 7.10 (tt, J=9.5, 4.8 Hz, 1H), 3.64-3.48 (m, 2H), 1.56 (d, J=6.1Hz, 4H), 1.38 (d, J=7.2 Hz, 7H), 0.92 (p, J=7.6 Hz, 3H); ESIMS m/z 317([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 62:

tert-Butyl (2,6-difluoro-3-nitrophenyl)(methyl)carbamate (C253)

Isolated as a yellow oil (0.56 g, 76%): ¹H NMR (400 MHz, DMSO-d₆)rotamers δ 8.32-8.19 (m, 1H), 7.49 (td, J=9.2, 1.9 Hz, 1H), 3.15 (s,1H), 3.11 (s, 2H), 1.48 (s, 3H), 1.31 (s, 6H); ¹⁹F NMR (376 MHz,DMSO-d₆) rotamers δ −106.79 (d, J=11.4 Hz), −107.54 (d, J=11.3 Hz),−121.48 (d, J=11.4 Hz), −122.14 (d, J=11.4 Hz).

The following compounds were prepared in like manner to the procedureoutlined in Example 65:

tert-ButylN-tert-butoxycarbonyl-N-[5-[(2-chloro-3-fluoro-5-nitro-benzoyl)amino]-2,4-difluoro-phenyl]carbamate(C254)

Isolated as a yellow solid (3.943 g, 85%): mp 172-175° C.; ¹H NMR (400MHz, DMSO-d₆) δ 10.74 (s, 1H), 8.52 (dd, J=8.8, 2.6 Hz, 1H), 8.44 (dd,J=2.6, 1.4 Hz, 1H), 7.90 (t, J=8.1 Hz, 1H), 7.57 (t, J=10.2 Hz, 1H),1.42 (s, 18H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.73, −118.21, −118.22,−121.44, −121.46; HRMS-ESI (m/z) [M+]⁺ calcd for C₂₃H₂₃ClF₃N₃O₇,545.1177; found, 545.1179.

The following compounds were prepared in like manner to the procedureoutlined in Example 67:

tert-Butyl (3-amino-2,6-difluorophenyl)(methyl)carbamate (C255)

Isolated as a white solid (0.45 g, 89%): ¹H NMR (400 MHz, CDCl₃)rotamers δ 6.72 (td, J=9.1, 1.9 Hz, 1H), 6.68-6.58 (m, 1H), 3.59 (s,2H), 3.16 (s, 3H), 1.53 (s, 2H), 1.37 (s, 7H); ¹⁹F NMR (376 MHz, CDCl₃)rotamers δ −132.31, −132.53, −138.84, −139.43; EIMS m/z 258.

tert-Butyl N-(5-amino-2-chloro-phenyl)-N-tert-butoxycarbonyl-carbamate(C256)

Isolated as a grey solid (1.7 g, 78%): ¹H NMR (400 MHz, CDCl₃) δ 7.15(d, J=8.5 Hz, 1H), 6.62-6.51 (m, 2H), 3.74 (s, 2H), 1.42 (s, 18H); ¹³CNMR (101 MHz, CDCl₃) δ 150.87, 145.76, 137.39, 129.65, 121.50, 116.14,115.67, 82.71, 27.85; ESIMS m/z 341 ([M−H]⁻).

tert-ButylN-(4-amino-2,6-dichloro-phenyl)-N-tert-butoxycarbonyl-carbamate (C257)

Isolated as a tan solid (1.88 g, 85%): ¹H NMR (400 MHz, CDCl₃) δ 6.64(s, 2H), 3.95 (s, 2H), 1.41 (s, 18H); ¹³C NMR (101 MHz, CDCl₃) δ 150.32,147.10, 134.34, 125.31, 113.81, 82.64, 27.77; ESIMS m/z 376 ([M−H]⁻).

tert-Butyl N-(4-amino-2-chloro-phenyl)-N-tert-butoxycarbonyl-carbamate(C258)

Isolated as a tan solid (1.96 g, 93%): ¹H NMR (400 MHz, CDCl₃) δ 6.93(d, J=8.5 Hz, 1H), 6.71 (d, J=2.6 Hz, 1H), 6.52 (dd, J=8.5, 2.6 Hz, 1H),3.80 (s, 2H), 1.41 (s, 18H); ¹³C NMR (101 MHz, CDCl₃) δ 151.33, 146.96,132.95, 130.03, 127.62, 115.23, 113.59, 82.43, 27.86; ESIMS m/z 341([M−H]⁻).

tert-Butyl N-(4-amino-2-cyano-phenyl)-N-tert-butoxycarbonyl-carbamate(C259)

Isolated as a white solid (2.45 g, 85%): ¹H NMR (300 MHz, CDCl₃) δ 7.01(dd, J=8.6, 0.4 Hz, 1H), 6.94-6.76 (m, 2H), 4.10 (d, J=7.1 Hz, 2H), 1.43(s, 18H); ¹³C NMR (75 MHz, CDCl₃) δ 150.99, 146.11, 132.35, 130.02,119.18, 117.76, 116.21, 113.30, 83.42, 27.85; ESIMS m/z 332 ([M−H]⁻).

tert-ButylN-(4-amino-2,3-dimethyl-phenyl)-N-tert-butoxycarbonyl-carbamate (C260)

Isolated as a white solid (0.19 g, 38%): ¹H NMR (400 MHz, CDCl₃) δ 6.76(d, J=8.3 Hz, 1H), 6.53 (d, J=8.4 Hz, 1H), 3.18 (s, 2H), 2.08 (d, J=1.9Hz, 6H), 1.42 (s, 18H); ESIMS m/z 335 ([M−H]⁻).

tert-ButylN-[4-amino-2-(trifluoromethyl)phenyl]-N-tert-butoxycarbonyl-carbamate(C261)

Isolated as a white solid (0.19 g, 38%): ¹H NMR (400 MHz, CDCl₃) δ6.99-6.88 (m, 2H), 6.78 (dd, J=8.5, 2.7 Hz, 1H), 3.99 (s, 2H), 1.38 (s,18H); ¹⁹F NMR (376 MHz, CDCl₃) δ −61.98; ESIMS m/z 375 ([M−H]⁻).

tert-Butyl (5-amino-2-methylphenyl)carbamate (C262)

Isolated as a brown foam (1.33 g, 91%): ¹H NMR (400 MHz, CDCl₃) δ 6.96(d, J=8.1 Hz, 1H), 6.70 (s, 1H), 6.56 (dd, J=8.1, 2.5 Hz, 1H), 6.44 (s,1H), 3.48 (s, 2H), 2.06 (s, 3H), 1.43 (s, 9H); ESIMS m/z 221 ([M−H]⁻).

tert-Butyl N-(3-amino-2-methyl-phenyl)-N-tert-butoxycarbonyl-carbamate(C263)

Isolated as a white solid (0.98 g, 89%): ¹H NMR (400 MHz, CDCl₃) δ 6.98(t, J=7.9 Hz, 1H), 6.63 (dd, J=8.0, 1.1 Hz, 1H), 6.55 (dd, J=7.8, 1.1Hz, 1H), 3.61 (s, 2H), 1.99 (s, 3H), 1.41 (s, 18H); ¹³C NMR (101 MHz,CDCl₃) δ 151.83, 145.13, 138.90, 126.28, 120.32, 118.63, 114.63, 82.19,27.92, 11.37; ESIMS m/z 323 ([M+H]⁺).

tert-ButylN-(5-amino-2,4-difluoro-3-methyl-phenyl)-N-tert-butoxycarbonyl-carbamate(C264)

Isolated as a tan solid (0.71 g, 83%): ¹H NMR (400 MHz, CDCl₃) δ6.49-6.40 (m, 1H), 3.56 (s, 2H), 2.19 (t, J=2.1 Hz, 3H), 1.44 (s, 18H);¹⁹F NMR (376 MHz, CDCl₃) δ −135.31, −135.93; ESIMS m/z 359 ([M+H]⁺).

N-(3-Amino-2,6-difluorophenyl)-N-ethyl-2,2-difluoroacetamide (C265)

Isolated as a gold oil (0.36 g, 86%): ¹H NMR (400 MHz, CDCl₃) δ6.94-6.75 (m, 2H), 5.80 (t, J=53.5 Hz, 1H), 3.92-3.66 (m, 2H), 1.17 (tt,J=7.2, 1.1 Hz, 3H); ESIMS m/z 251 ([M+H]⁺).

N-(3-Amino-2,6-difluorophenyl)-N-methylacetamide (C266)

Isolated as a brown oil (0.74 g, 76%): ¹H NMR (400 MHz, CDCl₃) δ6.96-6.67 (m, 2H), 3.94 (d, J=47.1 Hz, 2H), 3.20 (s, 3H), 1.91 (s, 3H);ESIMS m/z 231 ([M+H]⁺).

tert-Butyl (3-amino-2,6-difluorophenyl)(ethyl)carbamate (C267)

Isolated as a pink solid (0.36 g, 92%): ¹H NMR (400 MHz, CDCl₃) δ6.87-6.58 (m, 2H), 3.60 (dtt, J=18.7, 11.8, 5.8 Hz, 4H), 1.36 (s, 9H),1.11 (dt, J=14.6, 7.1 Hz, 3H); ESIMS m/z 273 ([M+H]⁺).

tert-Butyl (3-amino-2,6-difluorophenyl)(2-fluoroethyl)carbamate (C268)

Isolated as a gold oil (0.153 g, 81%): ¹H NMR (400 MHz, CDCl₃) δ6.86-6.55 (m, 2H), 4.68-4.43 (m, 2H), 3.85 (ddt, J=26.3, 11.8, 5.8 Hz,2H), 3.67 (s, 2H), 1.37 (s, 9H); ESIMS m/z 291 ([M+H]⁺).

tert-Butyl (3-amino-2,6-difluorophenyl)(propyl)carbamate (C269)

Isolated as a tan solid (0.310 g, 93%): ¹H NMR (400 MHz, CDCl₃) δ6.85-6.55 (m, 2H), 3.94-2.96 (m, 4H), 1.36 (s, 11H), 0.89 (q, J=7.8 Hz,3H); ESIMS m/z 287 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 68:

tert-Butyl N-tert-butoxycarbonyl-N-(2-chloro-5-nitro-phenyl)carbamate(C270)

Isolated as a white solid (2.26 g, 66%): ¹H NMR (400 MHz, CDCl₃) δ8.20-8.10 (m, 2H), 7.63 (d, J=8.8 Hz, 1H), 1.42 (s, 18H); ¹³C NMR (101MHz, CDCl₃) δ 149.83, 146.69, 140.24, 138.31, 130.25, 125.29, 123.68,84.04, 27.80; ESIMS m/z 373 ([M−H]⁻).

tert-ButylN-tert-butoxycarbonyl-N-(2,6-dichloro-4-nitro-phenyl)carbamate (C271)

Isolated as a gold oil (2.26 g, 73%): ¹H NMR (400 MHz, CDCl₃) δ 8.25 (s,2H), 1.41 (s, 18H); ¹³C NMR (101 MHz, CDCl₃) δ 152.16, 148.46, 146.81,141.22, 135.61, 123.13, 84.25, 27.69; ESIMS m/z 408 ([M−H]⁻).

tert-Butyl N-tert-butoxycarbonyl-N-(2-chloro-4-nitro-phenyl)carbamate(C272)

Isolated as a white solid (3.3 g, 97%): ¹H NMR (400 MHz, CDCl₃) δ 8.34(d, J=2.6 Hz, 1H), 8.17 (dd, J=8.7, 2.5 Hz, 1H), 7.43 (d, J=8.7 Hz, 1H),1.41 (s, 18H); ¹³C NMR (101 MHz, CDCl₃) δ 149.57, 147.24, 143.02,134.09, 130.62, 124.92, 122.33, 83.99, 27.76; ESIMS m/z 371 ([M−H]⁻).

tert-Butyl N-tert-butoxycarbonyl-N-(2-cyano-4-nitro-phenyl)carbamate(C273)

Isolated as a yellow solid (3.0 g, 86%): ¹H NMR (300 MHz, CDCl₃) δ 8.56(d, J=2.6 Hz, 1H), 8.47 (dd, J=8.8, 2.6 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H),1.47 (s, 18H); ¹³C NMR (75 MHz, CDCl₃) δ 149.52, 147.35, 146.52, 130.85,128.04, 128.01, 114.68, 114.00, 85.19, 27.81; ESIMS m/z 362 ([M−H]⁻).

tert-ButylN-tert-butoxycarbonyl-N-(2,3-dimethyl-4-nitro-phenyl)carbamate (C274)

Isolated as a white solid (0.52 g, 25%): ¹H NMR (400 MHz, CDCl₃) δ 7.63(d, J=8.6 Hz, 1H), 7.09 (d, J=8.6 Hz, 1H), 2.42 (s, 3H), 2.20 (s, 3H),1.42 (s, 18H); ¹³C NMR (101 MHz, CDCl₃) δ 150.90, 150.17, 141.64,137.39, 131.88, 126.47, 121.86, 83.36, 27.89, 15.94, 14.65; ESIMS m/z365 ([M−H]⁻).

tert-ButylN-tert-butoxycarbonyl-N-[4-nitro-2-(trifluoromethyl)phenyl]carbamate(C275)

Isolated as a yellow solid (2.93 g, 94%): ¹H NMR (400 MHz, CDCl₃) δ 8.58(d, J=2.6 Hz, 1H), 8.45 (dd, J=8.7, 2.6 Hz, 1H), 7.50 (d, J=8.7 Hz, 1H),1.39 (s, 18H); ¹⁹F NMR (376 MHz, CDCl₃) δ −62.25; ESIMS m/z 405([M−H]⁻).

tert-Butyl (2-methyl-5-nitrophenyl)carbamate (C276)

Isolated as a white solid (1.58 g, 63%): ¹H NMR (400 MHz, CDCl₃) δ 8.21(s, 1H), 8.14 (dd, J=8.5, 2.3 Hz, 2H), 7.43 (d, J=8.4 Hz, 1H), 2.40 (s,3H), 1.45 (s, 9H); ¹³C NMR (101 MHz, CDCl₃) δ 151.02, 146.64, 138.69,131.30, 123.88, 123.38, 84.52, 27.86, 18.10; ESIMS m/z 253 ([M+H]⁺).

tert-Butyl N-tert-butoxycarbonyl-N-(2-methyl-3-nitro-phenyl)carbamate(C277)

Isolated as a white solid (1.15 g, 31%): ¹H NMR (400 MHz, CDCl₃) δ7.91-7.81 (m, 1H), 7.41-7.25 (m, 2H), 2.37 (s, 3H), 1.41 (s, 18H); ESIMSm/z 353 ([M+H]+).

tert-ButylN-tert-butoxycarbonyl-N-(2,4-difluoro-3-methyl-5-nitro-phenyl)carbamate(C278)

Isolated as a gold solid (0.87 g, 40%): ¹H NMR (400 MHz, CDCl₃) δ 7.88(t, J=7.7 Hz, 1H), 2.32 (t, J=2.2 Hz, 3H), 1.46 (s, 18H); ¹⁹F NMR (376MHz, CDCl₃) δ −108.86, −108.91, −115.35, −115.39; ESIMS m/z 389([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 70:

N-(3-Amino-2,4,6-trifluorophenyl)acetamide (C279)

Isolated as a tan solid (2.8 g, 37%-three steps from2,4,6-trifluoroaniline): ¹H NMR (400 MHz, DMSO-d₆) δ 9.50 (s, 1H),7.11-7.00 (m, 1H), 5.07 (s, 2H), 2.04 (s, 3H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −131.69, −131.69, −131.72, −131.73, −134.98, −135.69,−135.70, −135.72, −135.73; ESIMS m/z 205 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example R4:

(1R,3R)-3-(3-Bromo-4-fluorophenyl)-2,2-dichlorocyclopropane-1-carboxylicacid (C243)

Isolated as a white solid (4.0 g, 40%): ¹H NMR (400 MHz, CDCl₃) δ 7.53(d, J=2.1 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.17 (dd, J=8.4, 2.1 Hz, 1H),3.43 (d, J=8.2 Hz, 1H), 2.86 (d, J=8.3 Hz, 1H); ESIMS m/z 343 ([M−H]⁻).Racemictrans-3-(3-Bromo-4-fluorophenyl)-2,2-dichlorocyclopropane-1-carboxylicacid can be prepared via methods described in U.S. Patent ApplicationPublication US20160304522A1 (C430).

(1R,3R)-2,2-Dichloro-3-(4-chloro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (C244)

Isolated as a white solid (0.37 g, 25%, 97% ee): ¹H NMR (400 MHz,DMSO-d₆) δ 13.41 (s, 1H), 7.96 (d, J=1.6 Hz, 1H), 7.79-7.71 (m, 2H),3.69-3.50 (m, 2H).

(1R,3R)-2,2-Dichloro-3-(3-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (C280)

Isolated as a white solid (3.4 g, 95% ee, 26% yield): ¹H NMR (400 MHz,CDCl₃) δ 10.38 (s, 1H), 7.66-7.59 (m, 1H), 7.57-7.44 (m, 3H), 3.55 (d,J=8.3 Hz, 1H), 2.94 (d, J=8.3 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ−62.70; ESIMS m/z 298 ([M−H]⁻).

(1R,3R)-2,2-Dichloro-3-(3-fluoro-5-(trifluoromethyl)phenyl)cyclopropane-1-carboxylicacid (C281)

Isolated as a white solid (2.5 g, 95% ee, 24% yield): ¹H NMR (400 MHz,CDCl₃) δ 10.93 (s, 1H), 7.34 (dd, J=7.1, 1.9 Hz, 2H), 7.20 (dt, J=8.8,2.0 Hz, 1H), 3.54 (d, J=8.3 Hz, 1H), 2.93 (d, J=8.3 Hz, 1H); ¹⁹F NMR(376 MHz, CDCl₃) δ −62.86, −109.50; ESIMS m/z 316 ([M−H]⁻).

Example 82 Preparation ofN-(3-acetamido-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1505)

N-(3-Amino-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1336) (0.041 g, 0.069 mmol) and sodium bicarbonate (0.029 g, 0.343mmol) were weighed into a 1-dram vial containing a stir bar. Ethylacetate (0.7 mL) was added, and acetyl chloride (6 μL, 0.084 mmol) wasadded via syringe. The heterogeneous mixture was allowed to stir for 3hours at room temperature. The reaction mixture was diluted with ethylacetate and saturated aqueous sodium bicarbonate; the layers wereseparated; and the organic layer was dried over sodium sulfate.Filtration and concentration gave the title compound as a white powder(0.044 g, 100%).

The following compounds were prepared in like manner to the procedureoutlined in Example 82:

N-(3-Acetamido-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1520)

Isolated as a white powder (0.047 g, 98%).

N-(3-Acetamido-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzamide(F1522)

Isolated as a tan powder (0.044 g, 98%).

N-(3-Acetamido-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1523)

Isolated as a tan powder (0.052 g, 100%).

N-(3-Acetamido-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1524)

Isolated as a tan solid (0.053 g, 92%).

N-(3-Acetamido-2,6-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1525)

Isolated as a tan powder (0.036 g, 91%).

N-(3-Acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1543)

Isolated as a tan powder (0.029 g, 97%).

N-(3-Acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1544)

Isolated as a tan powder (0.052 g, 94%).

N-(3-acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1545)

Isolated as a tan powder (0.039 g, 99%).

N-(5-Acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,4-dichlorophenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1546)

Isolated as a peach-colored powder (0.044 g, 98%).

N-(5-Acetamido-2,4-difluorophenyl)-3-((1R,3R)-2,2-dichloro-3-(3,4,5-trichlorophenyl)cyclopropane-1-carboxamido)-5-methylbenzamide(F1547)

Isolated as an off-white solid (0.048 g, 78%).

N-(5-Acetamido-2,4-difluorophenyl)-2-chloro-5-((1R,3R)-2,2-dichloro-3-(4-fluoro-3-(trifluoromethyl)phenyl)cyclopropane-1-carboxamido)-3-methylbenzamide(F1548)

Isolated as an off-white solid (0.037 g, 94%).

Example 83 Preparation of6-chloro-3-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluoro-N-(4-fluorophenyl)benzamide(F1465)

Step 1: To a solution of tert-butyl(4-chloro-2-fluoro-3-((4-fluorophenyl)carbamoyl)phenyl)carbamate (C310;0.066 g, 0.172 mmol) in dichloromethane (1 mL) was added hydrogenchloride (0.431 mL, 1.724 mmol) as a 4 M solution in dioxane, and theresulting turbid mixture was stirred at room temperature for 16 hours.The solvent was evaporated under reduced pressure and the residue wassuspended in dichloromethane and concentrated under a stream of nitrogento give the intermediate hydrochloride salt which was used immediatelyin the next step.

Step 2: To a mixture of(1R,3R)-2,2-dichloro-3-(4-chloro-3-fluorophenyl)cyclopropane-1-carboxylicacid (C93; 0.049 g, 0.172 mmol) and the freshly prepared intermediateaniline hydrochloride in ethyl acetate (1 mL) were added pyridine (0.074mL, 0.69 mmol) followed by a 50% solution of2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (0.103mL, 0.345 mmol) in ethyl acetate, and the resulting light-orangesolution was warmed to 50° C. and stirred for 16 hours. The reactionmixture was concentrated under a stream of nitrogen, and the resultingred, viscous oil was purified by automated flash chromatography (silicagel; 0450% ethyl acetate in hexanes). The resulting glassy oil wasdissolved/suspended in diethyl ether (1 mL) and treated with hexanesuntil turbid (few drops). The solvents were evaporated under a stream ofnitrogen to give the title compound as a light tan solid (0.081 mg,85%).

The following compounds were prepared in like manner to the procedureoutlined in Example 83:

6-Chloro-3-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-2-fluorobenzamide(F1464)

Isolated as a white solid (0.036 g, 61%).

6-Chloro-3-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluoro-N-phenylbenzamide(F1466)

Isolated as a white solid (0.076 g, 77%).

N-(3-Amino-2,4-difluorophenyl)-6-chloro-3-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluorobenzamide(F1508)

Isolated as a white solid (0.028 g, 41%).

6-Chloro-3-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-N-ethyl-2-fluorobenzamide(F2071)

Isolated as a white solid (0.024 g, 55%).

6-Chloro-3-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluoro-N-(2,2,2-trifluoroethyl)benzamide(F2072)

Isolated as a white solid (0.030 g, 70%).

6-Chloro-3-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluoro-N-(2,2,3,3,3-pentafluoropropyl)benzamide(F2073)

Isolated as a white solid (0.038 g, 77%).

6-Chloro-N-(3-chloropropyl)-3-((1R,3R)-2,2-dichloro-3-(3-chloro-4-fluorophenyl)cyclopropane-1-carboxamido)-2-fluorobenzamide(F2074)

Isolated as a white solid (0.028 g, 76%).

Example 84 Preparation oftrans-2-chloro-5-(2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-3-fluorobenzoicacid (C282)

To a stirred solution oftrans-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxylic acid(C1 in U.S. Patent Application Publication US20160304522A1; 0.25 g, 0.83mmol) in ethyl acetate (15 mL) were added5-amino-2-chloro-3-fluorobenzoic acid (C196; 0.15 g, 0.83 mmol),2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (50%solution in ethyl acetate; 1 mL, 3.34 mmol), and pyridine (0.8 mL, 4.18mmol). The reaction mixture was stirred at room temperature for 16hours. The reaction mixture was filtered through a pad of Celite®, andthe pad was washed with ethyl acetate. The filtrate was concentratedunder reduced pressure. The title compound was isolated as a pale yellowliquid (0.4 g) which was used in the next step without furtherpurification: ESIMS m/z 468.90 ([M−H]⁻).

Example 85 Supercritical Fluid Chromatography (SFC) purification of(1R,3R)-2,2-dichloro-3-(3,4,5-trifluorophenyl)cyclopropane-1-carboxylicacid (C283) and(1S,3S)-2,2-dichloro-3-(3,4,5-trifluorophenyl)cyclopropane-1-carboxylicacid (C284)

Racemic(trans)-2,2-dichloro-3-(3,4,5-trifluorophenyl)cyclopropane-1-carboxylicacid (U.S. Patent Application Publication US20160304522A1 (C228); 2.29g) was separated by Preparative SFC on a Chiralpak IE column (30×250 mm,5 μm) using 90:10 CO₂/0.5% isopropylamine in isopropanol and 100.0 barback pressure to give the title compounds: (C283) (0.9 g, peak 2);(C284) (0.9 g, peak 1).

The following compounds were prepared in like manner to the procedureoutlined in Example 85:

(1R,3R)-2,2-Dichloro-3-(3,4-difluorophenyl)cyclopropane-1-carboxylicacid (C285)

(1.5 g, peak 2): ¹H NMR (300 MHz, DMSO-d₆) δ 13.36 (br s, 1H), 7.58(ddd, J=2.0, 7.7, 11.9 Hz, 1H), 7.45 (td, J=8.6, 10.6 Hz, 1H), 7.32 (brd, J=1.8 Hz, 1H), 3.50-3.40 (m, 2H); ESIMS m/z 264.81 ([M−H]⁻). Thetitle compound was obtained via resolution of racemictrans-2,2-dichloro-3-(3,4-difluorophenyl)cyclopropane-1-carboxylic acid(U.S. Patent Application Publication US20160304522A1 (C421)).

(1S,3S)-2,2-Dichloro-3-(3,4-difluorophenyl)cyclopropane-1-carboxylicacid (C286)

(1.5 g, peak 1): ¹H NMR (300 MHz, DMSO-d₆) δ 13.36 (br s, 1H), 7.58(ddd, J=2.0, 7.8, 11.8 Hz, 1H), 7.45 (td, J=8.4, 10.6 Hz, 1H), 7.36-7.26(m, 1H), 3.52-3.42 (m, 2H); ESIMS m/z 264.81 ([M−H]⁻). The titlecompound was obtained via resolution of racemictrans-2,2-dichloro-3-(3,4-difluorophenyl)cyclopropane-1-carboxylic acid(U.S. Patent Application Publication US20160304522A1 (C421)).

Example 86 Preparation ofN-(5-amino-2,4-difluorophenyl)-2,2-difluoroacetamide (C287)

2,2-Difluoroacetic anhydride (2 mL, 2.87 mmol) was added to2,4-difluoro-5-nitroaniline (0.5 g, 2.87 mmol) in a 40 mL glass vialwith stir bar. The reaction mixture was stirred overnight. The mixturewas dried and the crude product was dissolved in ethyl acetate (10 mL).Palladium (5% on carbon, 500 mg) was added to the vial, and the mixturewas stirred overnight under a balloon of hydrogen. The mixture wasfiltered through a pad of Celite®, rinsed with ethyl acetate and thesolvent removed under reduced pressure. The title compound was isolatedas a brown solid (0.354 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H),7.79 (dd, J=9.2, 7.7 Hz, 1H), 6.87 (t, J=10.3 Hz, 1H), 6.02 (t, J=54.2Hz, 1H), 3.71 (s, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −125.72, −134.01,−140.54, −140.54; ESIMS m/z 223 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 86:

N-(5-Amino-2,4-difluorophenyl)-2,2,2-trifluoroacetamide (C288)

Isolated as a grey solid (0.383 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 7.93(s, 1H), 7.74 (dd, J=9.0, 7.7 Hz, 1H), 6.89 (t, J=10.3 Hz, 1H), 3.35 (s,2H); ¹⁹F NMR (376 MHz, CDCl₃) δ −75.74, −133.08, −140.33; ESIMS m/z 241([M+H]⁺).

N-(5-Amino-2,4-difluorophenyl)acetamide (C289)

Isolated as a brown solid (1.06 g, 90%): ¹H NMR (400 MHz, CDCl₃) δ 7.82(dd, J=9.4, 7.9 Hz, 1H), 7.20 (s, 1H), 6.80 (t, J=10.5 Hz, 1H), 3.63 (s,2H), 2.19 (s, 3H); ¹⁹F NMR (376 MHz, CDCl₃) δ −136.64, −141.55; ESIMSm/z 187 ([M+H]⁺).

N-(2-Amino-3-fluorophenyl)acetamide (C290)

Isolated as a pale solid (1.07 g, 90%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.26(s, 1H), 7.07 (dt, J=8.0, 1.3 Hz, 1H), 6.87 (ddd, J=11.0, 8.2, 1.4 Hz,1H), 6.52 (td, J=8.1, 5.9 Hz, 1H), 4.84 (s, 2H), 2.05 (s, 3H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −133.10.

N-(2-amino-5-fluorophenyl)acetamide (C291)

Isolated as a brown solid (1.06 g, 90%): ¹H NMR (400 MHz, DMSO-d₆) δ9.13 (s, 1H), 7.22 (dd, J=10.7, 2.8 Hz, 1H), 6.82-6.60 (m, 2H), 4.79 (s,2H), 2.05 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −127.99.

N-(5-Amino-2-fluorophenyl)acetamide (C292)

Isolated as a pale solid (1.07 g, 90%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.40(s, 1H), 7.13 (dd, J=6.9, 2.8 Hz, 1H), 6.84 (dd, J=10.9, 8.7 Hz, 1H),6.33-6.17 (m, 1H), 4.93 (s, 2H), 2.04 (s, 3H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −141.63.

N-(3-Amino-4-fluorophenyl)acetamide (C293)

Isolated as a pale solid (1.08 g, 90%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.66(s, 1H), 7.11 (dd, J=8.5, 2.6 Hz, 1H), 6.85 (dd, J=11.3, 8.7 Hz, 1H),6.63 (ddd, J=8.7, 4.0, 2.6 Hz, 1H), 5.11 (s, 2H), 1.98 (s, 3H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −141.04.

N-(2-Amino-4,6-difluorophenyl)acetamide (C294)

Isolated as a brown solid (1.06 g, 90%): ¹H NMR (400 MHz, DMSO-d₆) δ8.89 (s, 1H), 6.35-6.20 (m, 2H), 5.51 (s, 2H), 2.00 (s, 3H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −113.54, −113.56, −117.69, −117.71.

N-(2-Amino-3,5-difluorophenyl)acetamide (C295)

Isolated as a black solid (1.1 g, 90%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.31(s, 1H), 7.19 (dt, J=10.8, 2.3 Hz, 1H), 6.90 (ddd, J=11.5, 8.8, 2.9 Hz,1H), 4.78 (s, 2H), 2.07 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −126.81,−129.59.71.

N-(2-Amino-4,5-difluorophenyl)acetamide (C296)

Isolated as a gray solid (1.06 g, 90%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.11(s, 1H), 7.31 (dd, J=12.5, 8.8 Hz, 1H), 6.65 (dd, J=13.0, 8.1 Hz, 1H),5.07 (s, 2H), 2.03 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −142.62 (d,J=24.2 Hz), −153.98 (d, J=23.7 Hz).

N-(2-Amino-4,6-difluorophenyl)-2,2,2-trifluoroacetamide (C297)

Isolated as a brown solid (1.06 g, 90%): ¹H NMR (400 MHz, DMSO-d₆) δ14.52 (s, 1H), 7.67-7.18 (m, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −63.00,−113.06, −123.55.

N-(6-Amino-2,3-difluorophenyl)-2,2,2-trifluoroacetamide (C298)

Isolated as a brown solid (0.34 g, 50%): ¹H NMR (400 MHz, DMSO-d₆) δ14.51 (s, 1H), 7.51 (ddt, J=19.3, 13.2, 7.1 Hz, 2H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −63.06, −147.20, −153.46 (d, J=21.0 Hz).

N-(2-Amino-4,5-difluorophenyl)-2,2,2-trifluoroacetamide (C299)

Isolated as a brown solid (0.38 g, 50%): ¹H NMR (400 MHz, DMSO-d₆) δ14.30 (s, 1H), 7.84 (s, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −62.94,−62.95, −139.23, −142.16.

N-(2-Amino-3,5-difluorophenyl)-2,2,2-trifluoroacetamide (C300)

Isolated as a gray solid (0.38 g, 50%): ¹H NMR (400 MHz, DMSO-d₆) δ14.54 (s, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.31 (t, J=10.6 Hz, 1H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −63.00, −113.06, −123.56.

N-(2-Amino-5-fluorophenyl)-2,2,2-trifluoroacetamide (C301)

Isolated as a pale solid (0.39 g, 50%): ¹H NMR (400 MHz, DMSO-d₆) δ12.89 (s, 1H), 7.68 (ddd, J=12.2, 9.2, 3.5 Hz, 2H), 7.40 (td, J=9.3, 2.4Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −62.70, −118.54.

N-(5-Amino-2-fluorophenyl)-2,2,2-trifluoroacetamide (C302)

Isolated as a black solid (0.4 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 8.01(s, 1H), 7.66 (dd, J=6.5, 2.8 Hz, 1H), 6.94 (dd, J=10.5, 8.8 Hz, 1H),6.45 (ddd, J=8.8, 4.2, 2.8 Hz, 1H); ¹⁹F NMR (376 MHz, CDCl₃) δ −75.79,−144.06.

N-(3-Amino-4-fluorophenyl)-2,2,2-trifluoroacetamide (C303)

Isolated as a gray solid (0.42 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 7.72(s, 1H), 7.22 (dd, J=7.8, 2.6 Hz, 1H), 6.97 (dd, J=10.5, 8.7 Hz, 1H),6.69 (ddd, J=8.7, 3.9, 2.7 Hz, 1H), 3.86 (s, 2H); ¹⁹F NMR (376 MHz,CDCl₃) δ −75.74, −136.95.

N-(3-Amino-5-fluorophenyl)-2,2,2-trifluoroacetamide (C304)

Isolated as a gray solid (0.40 g, 50%): ¹H NMR (400 MHz, CDCl₃) δ 7.71(s, 1H), 6.80 (td, J=2.0, 0.7 Hz, 1H), 6.63 (dt, J=9.9, 2.1 Hz, 1H),6.25 (dt, J=10.3, 2.1 Hz, 1H), 3.90 (s, 2H); ¹⁹F NMR (376 MHz, CDCl₃) δ−75.79, −110.83.

N-(2-Amino-3-fluorophenyl)-2,2,2-trifluoroacetamide (C305)

Isolated as a brown solid (0.39 g, 50%): ¹H NMR (400 MHz, DMSO-d₆) δ14.36 (s, 1H), 7.51 (s, 1H), 7.40 (td, J=8.1, 4.8 Hz, 1H), 7.20 (t,J=9.5 Hz, 1H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −62.86, −127.62.

N-(2-Amino-6-fluorophenyl)-2,2,2-trifluoroacetamide (C306)

Isolated as a gray solid (0.4 g, 50%): ¹H NMR (400 MHz, DMSO-d₆) δ 14.33(s, 1H), 7.60-7.43 (m, 1H), 7.44-7.32 (m, 1H), 7.20 (d, J=9.0 Hz, 1H);¹⁹F NMR (376 MHz, DMSO-d₆) δ −62.74, −62.75, −62.87, −127.60.

Example 87 Preparation ofN-(3-amino-2,4-difluorophenyl)-2,2-difluoroacetamide hydrochloride(C307)

To a solution oftert-butyl-N-(3-amino-2,6-difluoro-phenyl)-N-tert-butoxycarbonyl-carbamate(C182) (1.0 g, 2.90 mmol) in dichloromethane (30 mL) was added2,2-difluoroacetic anhydride (2.5 mL, 3.59 mmol). The reaction mixturewas stirred overnight at room temperature and then concentrated underreduced pressure. The crude product was dissolved in dichloromethane (30mL). Hydrochloric acid (4 M in dioxane, 7.25 mL) was added to thesolution, and the reaction mixture was stirred at room temperature for 6hours. The precipitate that formed was filtered and washed with colddichloromethane. The title compound was isolated as a white solid (0.74g, 98%): ¹H NMR (400 MHz, DMSO-d₆) δ 10.47 (s, 1H), 6.91 (ddd, J=10.7,8.9, 1.9 Hz, 1H), 6.76 (td, J=8.5, 5.5 Hz, 1H), 6.44 (t, J=53.5 Hz, 1H),5.09 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −125.40, −133.15 (d, J=14.3Hz), −138.66 (d, J=14.4 Hz).

The following compounds were prepared in like manner to the procedureoutlined in Example 87:

N-(3-Amino-2,4-difluorophenyl)-2,2,2-trifluoroacetamide hydrochloride(C308)

Isolated as a brown solid (0.80 g, 99%): ¹H NMR (400 MHz, DMSO-d₆) δ11.09 (s, 1H), 6.95 (ddd, J=10.7, 8.8, 1.9 Hz, 1H), 6.57 (td, J=8.4, 5.4Hz, 1H), 5.56 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −73.91, −131.57 (d,J=15.6 Hz), −137.08 (d, J=15.6 Hz).

N-(3-Amino-2,4-difluorophenyl)acetamide hydrochloride (C309)

Isolated as a brown solid (0.60 g, 93%): ¹H NMR (400 MHz, DMSO-d₆) δ9.55 (s, 1H), 6.91 (td, J=8.5, 5.7 Hz, 1H), 6.83 (ddd, J=10.7, 8.9, 1.8Hz, 1H), 5.94 (s, 3H), 2.04 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−135.33 (d, J=12.4 Hz), −140.18 (d, J=12.3 Hz).

Example 88 Preparation of tert-butyl(4-chloro-2-fluoro-3-((4-fluorophenyl)carbamoyl)phenyl)carbamate (C310)

To a solution of 3-((tert-butoxycarbonyl)amino)-6-chloro-2-fluorobenzoicacid (C318; 85.0 mg, 0.293 mmol) and 4-fluoroaniline (34.2 mg, 0.308mmol) in ethyl acetate (2.5 mL) were added pyridine (0.094 mL, 0.880mmol) followed by 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (0.35 mL, 0.587 mmol), and the resulting light-yellowsolution was warmed to 50° C. and stirred for 8 hours. The reactionmixture was concentrated under a stream of nitrogen, and the resultingred-orange oil was purified by automated flash chromatography (silicagel; 0465% ethyl acetate in hexanes). The title compound was isolated asa white solid (0.075 g, 66%): mp 145-148° C.; ¹H NMR (400 MHz, DMSO-d₆)δ 10.83 (s, 1H), 9.32 (s, 1H), 7.80-7.64 (m, 3H), 7.36 (dd, J=8.8, 1.4Hz, 1H), 7.27-7.16 (m, 2H), 1.47 (s, 9H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−118.08, −124.58; ESIMS m/z 381 ([M−H]⁻).

The following compounds were prepared in like manner to the procedureoutlined in Example 88:

tert-Butyl (4-chloro-2-fluoro-3-(phenylcarbamoyl)phenyl)carbamate (C311)

Isolated as a white solid (0.085 g, 79%): mp 91-94° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 10.76 (s, 1H), 9.31 (s, 1H), 7.74 (t, J=8.7 Hz, 1H),7.71-7.66 (m, 2H), 7.42-7.29 (m, 3H), 7.21-7.06 (m, 1H), 1.47 (s, 9H);¹⁹F NMR (376 MHz, DMSO-d₆) δ −124.64; ESIMS m/z 363 ([M−H]⁻).

tert-Butyl(4-chloro-3-((2,4-difluorophenyl)carbamoyl)-2-fluorophenyl)carbamate(C312)

Isolated as a white solid (0.048 g, 40%): mp 136-139° C.; ¹H NMR (400MHz, DMSO-d₆) δ 10.66 (s, 1H), 9.31 (s, 1H), 7.81 (td, J=8.9, 6.1 Hz,1H), 7.74 (t, J=8.6 Hz, 1H), 7.43-7.32 (m, 2H), 7.18-7.10 (m, 1H), 1.47(s, 9H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −113.14, −113.16, −117.72,−117.74, −124.47; ESIMS m/z 399 ([M−H]⁻).

tert-Butyl(tert-butoxycarbonyl)(3-(3-((tert-butoxycarbonyl)amino)-6-chloro-2-fluorobenzamido)-2,6-difluorophenyl)carbamate(C313)

Isolated as a white solid (0.076 g, 34%): mp 83-88° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 10.75 (s, 1H), 9.30 (s, 1H), 7.88-7.68 (m, 2H), 7.35 (dd,J=8.8, 1.4 Hz, 1H), 7.32-7.23 (m, 1H), 1.47 (s, 9H), 1.40 (s, 18H); ¹⁹FNMR (376 MHz, DMSO-de) δ −123.39, −124.42, −126.90; ESIMS m/z 614([M−2H]⁻).

tert-Butyl (4-chloro-3-(ethylcarbamoyl)-2-fluorophenyl)carbamate (C314)

Isolated as a white solid (0.032 g, 34%): mp 145-147° C.; ¹H NMR (400MHz, DMSO-d₆) δ 9.21 (s, 1H), 8.66 (t, J=5.6 Hz, 1H), 7.65 (t, J=8.6 Hz,1H), 7.26 (dd, J=8.8, 1.5 Hz, 1H), 3.25 (qd, J=7.2, 5.5 Hz, 2H), 1.46(s, 9H), 1.10 (t, J=7.2 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −124.90;ESIMS m/z 315 ([M−H]⁻).

tert-Butyl(4-chloro-2-fluoro-3-((2,2,2-trifluoroethyl)carbamoyl)phenyl)-carbamate(C315)

Isolated as a white solid (0.035 g, 32%): mp 177-180° C.; ¹H NMR (400MHz, DMSO-d₆) δ 9.42 (t, J=6.2 Hz, 1H), 9.27 (s, 1H), 7.70 (t, J=8.6 Hz,1H), 7.31 (dd, J=8.8, 1.4 Hz, 1H), 4.19-4.00 (m, 2H), 1.46 (s, 9H); ¹⁹FNMR (376 MHz, DMSO-d₆) δ −70.42, −124.62; ESIMS m/z 369 ([M−H]⁻).

tert-Butyl(4-chloro-2-fluoro-3-((2,2,3,3,3-pentafluoropropyl)carbamoyl)phenyl)-carbamate(C316)

Isolated as a white solid (0.047 g, 38%): mp 152-155° C.; ¹H NMR (400MHz, DMSO-d₅) δ 9.44 (t, J=6.3 Hz, 1H), 9.26 (s, 1H), 7.70 (t, J=8.6 Hz,1H), 7.31 (dd, J=8.9, 1.4 Hz, 1H), 4.15 (td, J=15.7, 5.7 Hz, 2H), 1.46(s, 9H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −83.41, −120.04, −124.47; ESIMSm/z 419 ([M−H]⁻).

tert-Butyl(4-chloro-3-((3-chloropropyl)carbamoyl)-2-fluorophenyl)carbamate (C317)

Isolated as a white solid (0.032 g, 30%): mp 126-128° C.; ¹H NMR (400MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.77 (t, J=5.6 Hz, 1H), 7.66 (t, J=8.6 Hz,1H), 7.28 (dd, J=8.8, 1.4 Hz, 1H), 3.70 (t, J=6.6 Hz, 2H), 3.40-3.36 (m,2H), 1.95 (p, J=6.6 Hz, 2H), 1.46 (s, 9H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−124.88; ESIMS m/z 363 ([M−2H]⁻).

Example 89 Preparation of3-((tert-butoxycarbonyl)amino)-6-chloro-2-fluorobenzoic acid (C318)

To a suspension of ethyl3-[bis(tert-butoxycarbonyl)amino]-6-chloro-2-fluorobenzoate (C319; 7.57g, 18.1 mmol) in a 2:1 mixture of tetrahydrofuran (48 mL) and water (24mL) was added lithium hydroxide monohydrate (2.28 g, 54.3 mmol), and theresulting turbid mixture was vigorously stirred for 16 hours at roomtemperature, at which point LC-MS analysis indicated only startingmaterial and the starting material with one of the Boc groups cleaved.The reaction mixture was diluted with methanol (25 mL) and the mixturewas stirred at room temperature for 16 hours, at which point LC-MSindicated full consumption of the ester starting material. The organicswere evaporated under reduced pressure, and the residual aqueous mixture(cream colored precipitate) was diluted with ethyl acetate (˜200 mL) andvigorously stirred while the pH was adjusted (6-7) by the dropwiseaddition of 1 N aqueous hydrogen chloride (˜35 mL). The phases wereseparated and the aqueous phase was extracted with additional ethylacetate (2×50 mL). The combined organic extracts were washedsuccessively with water (100 mL) and brine (2×75 mL), dried over sodiumsulfate, filtered, and concentrated. The title compound was isolated asa colorless, glassy solid (1.465 g, 27%): mp 79-84° C.; ¹H NMR (400 MHz,DMSO-d₆) δ 9.12 (s, 1H), 7.58 (t, J=8.6 Hz, 1H), 7.21 (dd, J=8.8, 1.4Hz, 1H), 1.46 (s, 9H); ¹³C NMR (101 MHz, DMSO-d₆) δ 170.20, 163.68,152.78, 151.13, 148.66, 125.75, 125.63, 124.53, 124.50, 123.63, 79.62,59.64, 27.90, 20.65, 13.99; ¹⁹F NMR (376 MHz, DMSO-d₆) δ −124.86; ESIMSm/z 288 ([M−H]⁻).

Example 90 Preparation of ethyl3-[bis(tert-butoxycarbonyl)amino]-6-chloro-2-fluorobenzoate (C319)

To a solution of ethyl 3-amino-6-chloro-2-fluorobenzoate (C320; 8.5 g,39.1 mmol) in N,N-dimethylformamide (32.5 mL) were sequentially addedadded N,N-dimethylpyridin-4-amine (0.239 g, 1.95 mmol),N-ethyl-N-isopropylpropan-2-amine (20.4 mL, 117 mmol), and di-tert-butyldicarbonate (25.6 g, 117 mmol; added in portions), and the resultinglight yellow solution was stirred at room temperature for approximately16 hours. The reaction mixture was treated with additional di-tert-butyldicarbonate (3.00 g, 13.7 mmol), stirred for 3 hours at roomtemperature, and partitioned between ethyl acetate (200 mL) and 5%aqueous solution of sodium bicarbonate (600 mL). The phases wereseparated, and the aqueous phase was extracted with diethyl ether (150mL). Each of the organic extracts was washed with water (ethyl acetate:3×200 mL; diethyl ether: 2×100 mL). The extracts were combined, driedover sodium sulfate, filtered, and concentrated to a viscous, red oil.The crude oil was purified by automated flash chromatography (Silicagel; 0430% ethyl acetate in hexanes) to give the title compound asviscous, gold oil which slowly solidifies upon standing (12.55 g. 77%):mp 91-95° C.; ¹H NMR (400 MHz, CDCl₃) δ 7.25-7.13 (m, 2H), 4.45 (q,J=7.2 Hz, 2H), 1.45-1.36 (m, 21H); ¹³C NMR (101 MHz, CDCl₃) δ 162.51,156.15, 153.60, 150.19, 131.43, 131.38, 131.19, 131.17, 126.73, 126.60,125.14, 125.10, 123.16, 122.97, 83.74, 62.41, 27.81, 14.11; ¹⁹F NMR (376MHz, CDCl₃) δ −119.43.

Example 91 Preparation of ethyl 3-amino-6-chloro-2-fluorobenzoate (C320)

To a solution of 4-chloro-2-fluoroaniline (11 g, 76 mmol) in anhydroustetrahydrofuran (151 mL) cooled to −76° C. was added butyllithium (31.7mL, 79 mmol) as a 2.5 M solution in hexanes at a rate which maintainedthe temperature between below −68° C., and the resulting greenish-brownsolution was stirred at −75° C. for 45 minutes. The heterogeneous brownreaction mixture was treated with a tetrahydrofuran solution (50 mL) of1,2-bis(chlorodimethylsilyl)ethane (17.24 g, 80 mmol) at a rate whichmaintained the temperature between −68 and −75° C. Following theaddition, the resulting brown solution was stirred at −75° C. for 75minutes. The resulting brown solution was treated with butyllithium(31.7 mL, 79 mmol) at a rate which maintained the temperature below −70°C., and the resulting solution was stirred at −74° C. for 30 minutes.The cooling bath was removed and the reaction solution was allowed toslowly warm to 15° C. over approximately a 2-hour period.

The solution was cooled to −72° C. and treated dropwise withbutyllithium (31.7 mL, 79 mmol) at a rate which maintained thetemperature below −70° C. After stirring for 60 minutes at −74° C., theresulting amber-brown solution was treated with ethyl carbonochloridate(10.66 g, 98 mmol) dropwise at a rate which maintained the temperaturebelow −70° C., and the resulting dark solution was allowed to slowlywarm to room temperature as the dry ice was consumed.

The resulting heterogeneous mixture (tan ppt) was cooled to 0° C. andquenched by the cautious addition of 3 N aqueous hydrogen chloride (140mL, 0.42 mmol). The ice bath was removed and the resulting dark solutionwas stirred at room temperature for 60 minutes. The pH was adjusted to˜8 by the careful addition of solid sodium carbonate (˜28 g) and themixture was extracted with ethyl acetate (3×150 mL). The combinedextracts were washed with brine (3×100 mL), dried over sodium sulfate,filtered, and concentrated to a dark oil. The crude oil was purified byautomated flash chromatography (silica gel; 0430% ethyl acetate inhexanes) to give the title compound as a light-orange oil (8.96 g. 54%):¹H NMR (400 MHz, CDCl₃) δ 6.97 (dd, J=8.6, 1.5 Hz, 1H), 6.73 (t, J=8.9Hz, 1H), 4.43 (q, J=7.1 Hz, 2H), 3.84 (s, 2H), 1.40 (t, J=7.2 Hz, 3H);¹³C NMR (101 MHz, CDCl₃) δ 163.49, 149.38, 146.94, 133.85, 133.73,125.36, 125.32, 122.35, 122.18, 119.48, 119.44, 117.95, 117.90, 62.19,14.14; ¹⁹F NMR (376 MHz, CDCl₃) δ −134.47; EIMS m/z 217.

Example 92 Preparation of N-(3-amino-2,6-dichlorophenyl)acetamide (C321)

Step 1: Preparation of tert-butyl(3-acetamido-2,4-dichlorophenyl)carbamate.3-Acetamido-2,4-dichlorobenzoic acid (1 g, 4.03 mmol) was addedportionwise to a stirred solution of diphenylphosphoryl azide (1.47 g,5.34 mmol), and triethylamine (0.54 g, 5.34 mmol) in anhydroustert-butanol (25 mL). The resulting gold solution was heated at 80° C.for 1 hour, then cooled and quenched with water (20 mL). The resultingaqueous mixture was extracted with ethyl acetate (2×50 mL) and washedwith saturated aqueous sodium bicarbonate solution (50 mL) and saturatedaqueous sodium chloride solution (50 mL). The organic extracts weredried over anhydrous magnesium sulfate, filtered and concentrated undervacuum on a rotary evaporator. Purification by flash silica gel columnchromatography using 0-30% ethyl acetate in hexanes as eluent gave thetitle compound as a white solid (0.72 g, 44%): ¹H NMR (400 MHz, CDCl₃) δ8.02 (d, J=9.1 Hz, 1H), 7.32-7.25 (m, 2H), 6.96 (s, 1H), 2.23 (s, 3H),1.54 (s, 9H); ESIMS m/z 320 ([M+H]⁺).

Step 2: Preparation of N-(3-amino-2,6-dichlorophenyl)acetamide. 4 MHydrogen chloride in 1,4-dioxane (2.8 mL, 11.3 mmol) was added dropwiseto a stirred solution of tert-butyl(3-acetamido-2,4-dichlorophenyl)carbamate (0.72 g, 2.25 mmol) indichloromethane (5 mL). The resulting suspension of solid was stirredfor 11 hours at 23° C. and then concentrated under vacuum on a rotaryevaporator. The resulting crude product was slurried in dichloromethane(2 mL) and treated with triethylamine until a solution formed (˜0.3 mL).Purification by silica gel flash chromatography using 0-100% ethylacetate in hexanes as eluent provided the title compound as a whitesolid. (0.45 g, 87%): ¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (s, 1H), 7.13 (d,J=8.8 Hz, 1H), 6.73 (d, J=8.8 Hz, 1H), 5.54 (s, 2H), 2.02 (s, 3H); ¹³CNMR (101 MHz, DMSO-d₆) δ 168.34, 145.19, 133.52, 127.82, 119.20, 117.75,114.48, 22.92; ESIMS m/z 220 ([M+H]⁺).

Example 93 Preparation of5-amino-2-chloro-N-(2,2-difluoropropyl)benzamide (C322)

To a solution of 2-chloro-N-(2,2-difluoropropyl)-5-nitrobenzamide (C386;0.45 g, 1.61 mmol) in a mixture of tetrahydrofuran-ethanol-water (3:2:1,12 mL) were added iron powder (0.54 g, 9.71 mmol) and ammonium chloride(0.86 g, 16.18 mmol), and the reaction mixture was stirred at 80° C. for8 hours. The reaction mixture was filtered through a pad of Celite® andwashed with ethyl acetate (50 mL) and methanol (30 mL). The filtrate wasconcentrated under reduced pressure, and the residue was taken up inwater and made basic with sodium bicarbonate solution. The aqueous layerwas extracted with ethyl acetate (3×20 mL), and the organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. Purification by preparative high-performance liquidchromatography (HPLC) afforded the title compound as an off-white solid(0.24 g, 63%): mp 99-101° C.; ¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (t, J=6.4Hz, 1H), 7.06 (d, J=1.6, 7.2 Hz, 1H), 6.62-6.55 (m, 2H), 5.39 (s, 2H),3.68-3.58 (m, 2H), 1.63 (t, J=19.1 Hz, 3H); ESIMS m/z 249.10 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 93:

5-Amino-2-chloro-N-(2,2-difluorobutyl)benzamide (C323)

Isolated as an off-white solid (0.21 g, 52%): mp 82-84° C.; ¹H NMR (400MHz, DMSO-d₆) δ 8.64 (t, J=6.4 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H),6.62-6.54 (m, 2H), 5.39 (s, 2H), 3.66-3.61 (m, 2H), 2.04-1.83 (m, 2H),0.98 (t, J=7.6 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −102.95; ESIMS m/z263.12 ([M+H]⁺).

Ethyl 3-(5-amino-2-chlorobenzamido)-2,2-difluoropropanoate (C324)

Isolated as a yellow solid (0.095 g, 18%): mp 100-102° C.; ¹H NMR (400MHz, DMSO-d₆) δ 8.78 (t, J=6.4 Hz, 1H), 7.06 (d, J=8.0 Hz, 1H), 6.59(dd, J=2.4, 8.8 Hz, 1H), 6.55 (d, J=2.8 Hz, 1H), 5.42 (s, 2H), 4.28 (q,J=6.8 Hz, 2H), 3.93-3.84 (m, 2H), 1.28 (t, J=7.2 Hz, 3H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −109.55; ESIMS m/z 307.12 ([M+H]⁺).

5-Amino-2-chloro-N-(2,2-difluoro-2-phenylethyl)benzamide (C325)

Isolated as a brown solid (0.22 g, 37%): mp 109-111° C.; ¹H NMR (400MHz, DMSO-d₆) δ 8.71 (t, J=6.4 Hz, 1H), 7.61-7.46 (m, 5H), 7.03 (d,J=8.8 Hz, 1H), 6.57 (dd, J=2.8, 8.4 Hz, 1H), 6.50 (d, J=2.8 Hz, 1H),5.38 (s, 2H), 4.00-3.90 (m, 2H); ESIMS m/z 311.16 ([M+H]⁺).

5-Amino-2-chloro-N-(2-oxopropyl)benzamide (C326)

Isolated as an off-white solid (0.2 g, 57%): mp 118-120° C.; ¹H NMR (400MHz, DMSO-d₆) δ 8.54 (t, J=5.6 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.66 (d,J=2.4 Hz, 1H), 6.59 (dd, J=2.4, 8.4 Hz, 1H), 5.42 (s, 2H), 3.98 (d,J=5.6 Hz, 2H), 2.12 (s, 3H); ESIMS m/z 227.30 ([M+H]⁺).

5-Amino-2-chloro-N-(2-oxobutyl)benzamide (C327)

Isolated as an off-white solid (0.25 g, 26%): mp 91-93° C.; ¹H NMR (400MHz, DMSO-d₆) δ 8.52 (t, J=5.6 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.66 (d,J=2.8 Hz, 1H), 6.59 (d, J=2.4, 8.8 Hz, 1H), 5.42 (s, 2H), 3.99 (d, J=5.8Hz, 2H), 2.49-2.41 (m, 2H), 0.96 (t, J=7.2 Hz, 3H); ESIMS m/z 241.06([M+H]⁺).

5-Amino-2-chloro-N-(4-methyl-2-oxopentyl)benzamide (C328)

Isolated as an off-white solid (0.2 g, 23%): mp 115-117° C.; ¹H NMR (400MHz, DMSO-d₆) δ 8.50 (t, J=5.6 Hz, 1H), 7.06 (d, J=8.4 Hz, 1H), 6.66 (d,J=2.8 Hz, 1H), 6.59 (dd, J=2.4, 8.8 Hz, 1H), 5.43 (s, 2H), 3.97 (d,J=6.0 Hz, 2H), 2.36 (d, J=6.8 Hz, 2H), 2.13-1.99 (m, 1H), 0.88 (d, J=6.4Hz, 6H); ESIMS m/z 269.06 ([M+H]⁺).

5-Amino-2-chloro-N-(2-oxo-2-phenylethyl)benzamide (C329)

Isolated as an off-white solid (0.06 g, 17%): mp 132-134° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 8.54 (t, J=5.6 Hz, 1H), 8.03 (d, J=7.2 Hz, 2H),7.70-7.66 (m, 1H), 7.59-7.54 (m, 2H), 7.07 (d, J=8.4 Hz, 1H), 6.73 (d,J=2.8 Hz, 1H), 6.60 (dd, J=2.8, 8.4 Hz, 1H), 5.42 (s, 2H), 4.71 (d,J=6.0 Hz, 2H); ESIMS m/z 289.14 ([M+H]⁺).5-Amino-2-chloro-N-(2,2-difluoropropyl)-3-fluorobenzamide (C330)

Isolated as an off-white solid (0.2 g, 63%): mp 107-109° C.; ¹H NMR (400MHz, DMSO-d₆) δ 8.80 (t, J=6.4 Hz, 1H), 6.53 (dd, J=2.8, 12.0 Hz, 1H),6.43 (d, J=1.6 Hz, 1H), 5.73 (br s, 2H), 3.69-3.60 (m, 2H), 1.63 (t,J=18.8 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −93.66, −115.77; ESIMS m/z267.08 ([M+H]⁺).

5-Amino-2-chloro-N-(2,2-difluorobutyl)-3-fluorobenzamide (C331)

Isolated as an off-white solid (0.19 g, 53%): mp 79-81° C.; ¹H NMR (400MHz, DMSO-d₆) δ 8.81 (t, J=6.0 Hz, 1H), 6.56 (dd, J=2.8, 12.4 Hz, 1H),6.45-6.42 (m, 1H), 5.72 (br s, 2H), 3.70-3.60 (m, 2H), 1.97-1.86 (m,2H), 0.98 (t, J=8.0 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −103.09,−115.77; ESIMS m/z 281.14 ([M+H]⁺).

Ethyl 3-(5-amino-2-chloro-3-fluorobenzamido)-2,2-difluoropropanoate(C332)

Isolated as an off-white solid (0.12 g, 19%): mp 83-85° C.; ¹H NMR (400MHz, DMSO-d₆) δ 8.92 (t, J=6.4 Hz, 1H), 6.54 (dd, J=2.4, 11.6 Hz, 1H),6.42-6.40 (m, 1H), 5.76 (br s, 2H), 4.28 (q, J=7.2 Hz, 2H), 3.95-3.85(m, 2H), 1.28 (t, J=6.8 Hz, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −109.59,−115.63; ESIMS m/z 325.17 ([M+H]⁺).

5-Amino-2-chloro-3-fluoro-N-(2-oxobutyl)benzamide (C333)

Isolated as an off-white solid (0.14 g, 40%): mp 96-98° C.; ¹H NMR (400MHz, DMSO-d₆) δ 8.65 (t, J=6.0 Hz, 1H), 6.55-6.50 (m, 2H), 5.76 (br s,2H), 4.01 (d, J=5.6, Hz, 2H), 2.49-2.46 (m, 2H), 0.95 (t, J=7.2 Hz, 3H);¹⁹F NMR (376 MHz, DMSO-d₆) δ −115.66; ESIMS m/z 259.12 ([M+H]⁺).

5-Amino-2-chloro-3-fluoro-N-(4-methyl-2-oxopentyl)benzamide (C334)

Isolated as an off-white solid (0.32 g, 58%): mp 99-101° C.; ¹H NMR (400MHz, DMSO-d₆) δ 8.58 (t, J=6.0 Hz, 1H), 6.54-6.51 (m, 2H), 5.74 (br s,2H), 3.98 (d, J=6.0 Hz, 2H), 2.35 (d, J=6.8 Hz, 2H) 2.08-2.01 (m, 1H),0.88 (d, J=6.8 Hz, 6H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −115.68; ESIMS m/z287.15 ([M+H]⁺).

5-Amino-2-chloro-3-fluoro-N-(2-oxo-2-phenylethyl)benzamide (C335)

Isolated as an off-white solid (0.21 g, 57%): mp 147-149° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 8.67 (t, J=5.6 Hz, 1H), 8.04-8.01 (m, 2H),7.70-7.66 (m, 1H), 7.56 (t, J=8.0 Hz, 2H), 6.58-6.52 (m, 2H), 5.76 (brs, 2H), 4.72 (d, J=5.6 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −115.29;ESIMS m/z 307.19 ([M+H]⁺).

5-Amino-2-chloro-3-fluoro-N-(2-oxopropyl)benzamide (C336)

Isolated as an off-white solid (0.075 g, 30%): mp 126-128° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 8.65 (t, J=5.6 Hz, 1H), 6.55-6.50 (m, 2H), 5.76 (brs, 2H), 4.01 (d, J=6.0 Hz, 2H), 2.13 (s, 3H); ¹⁹F NMR (376 MHz, DMSO-d₆)δ −115.66; ESIMS m/z 245.03 ([M+H]⁺).

5-Amino 2-chloro-N-(2,2-difluoro-2-phenylethyl)-3-fluorobenzamide (C337)

Isolated as an off-white solid (0.25 g, 60%): mp 136-138° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 8.83 (t, J=6.4 Hz, 1H), 7.58-7.49 (m, 5H), 6.51(dd, J=2.4, 11.6 Hz, 1H), 6.36-6.31 (m, 1H), 5.72 (br s, 2H), 4.01-3.91(m, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −98.49, −115.60; ESIMS m/z 329.17([M+H]⁺).

Example 94 Preparation of5-amino-2-chloro-N-(2-oxo-2-(2,2,2-trifluoroethylamino)ethyl)benzamide(C338)

To a solution of 5-amino-2-chlorobenzoic acid (0.6 g, 3.49 mmol) indichloromethane (10 mL) were added sequentially2-amino-N-(2,2,2-trifluoroethyl)acetamide (C350; 0.8 g, 4.20 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2 g, 10.5mmol), diisopropylethylamine (1.73 mL, 10.5 mmol), and4-(dimethylamino)pyridine (cat.), and the reaction mixture was stirredat room temperature for 16 hours. The reaction mixture was concentratedunder reduced pressure. Purification by column chromatography (silicagel 100-200 mesh) eluting with 5-10% ethyl acetate in methanol affordedthe title compound as an off-white solid (0.28 g, 26%): mp 109-111° C.;¹H NMR (400 MHz, DMSO-d₆) δ 8.47 (t, J=5.6 Hz, 1H), 8.42 (t, J=6.0 Hz,1H), 7.05 (d, J=8.4 Hz, 1H), 6.68 (d, J=2.8 Hz, 1H), 6.58 (dd, J=2.4,8.8 Hz, 1H), 5.38 (m, 2H), 3.98-3.89 (m, 2H), 3.87 (d, J=6.0 Hz, 2H);ESIMS m/z 310.15 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 94:

5-Amino-2-chloro-N-(3-oxo-3-((2,2,2-trifluoroethyl)amino)propyl)benzamide(C339)

Isolated as an off-white solid (0.17 g, 15%): mp 148-150° C;¹H NMR (400MHz, DMSO-d₆) δ 8.56 (t, J=6.4 Hz, 1H), 8.22 (t, J=5.2 Hz, 1H), 7.04 (d,J=8.4 Hz, 1H), 6.58-6.54 (m, 2H), 5.33 (s, 2H), 3.92-3.84 (m, 2H),3.41-3.35 (m, 2H), 2.44 (t, J=7.2 Hz, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−70.71; ESIMS m/z 324.20 ([M+H]⁺).

5-Amino-2-chloro-N-(4-oxo-4-((2,2,2-trifluoroethyl)amino)butyl)benzamide(C340)

Isolated as an off-white solid (0.59 g, 25%): mp 136-138° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 8.46 (t, J=6.4 Hz, 1H), 8.22 (t, J=5.2 Hz, 1H),7.05-7.02 (m, 1H), 6.58-6.55 (m, 2H), 5.34 (s, 2H), 3.93-3.84 (m, 2H),3.28-3.14 (m, 2H), 2.23 (t, J=7.2 Hz, 2H), 1.75-1.68 (m, 2H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −70.85; ESIMS m/z 338.18 ([M+H]⁺).

5-Amino-2-chloro-N-(2-oxo-2-((3,3,3-trifluoropropyl)amino)ethyl)benzamide(C341)

Isolated as an off-white solid (0.98 g, 33%): mp 110-112° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 8.39 (t, J=6.0 Hz, 1H), 8.04 (t, J=5.6, 1H), 7.06(d, J=8.4 Hz, 1H), 6.68 (d, J=3.2 Hz, 1H), 6.58 (dd, J=2.4, 8.4 Hz, 1H),5.39 (s, 2H), 3.78 (d, J=6.0 Hz, 2H), 3.35-3.30 (m, 2H), 2.49-2.39 (m,2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −63.98; ESIMS m/z 324.13 ([M+H]⁺).

5-Amino-2-chloro-N-(3-oxo-3-((3,3,3-trifluoropropyl)amino)propyl)benzamide(C342)

Isolated as an off-white solid (0.83 g, 28%): mp 109-111° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 8.23 (t, J=5.6 Hz, 1H), 8.13 (t, J=5.6 Hz, 1H),7.04 (d, J=8.4 Hz, 1H), 6.57 (d, J=3.2 Hz, 1H), 6.56-6.54 (m, 1H), 5.36(s, 2H), 3.39-3.34 (m, 2H), 3.30-3.25 (m, 2H), 2.50-2.31(m, 4H); ¹⁹F NMR(376 MHz, DMSO-d₆) δ −63.98; ESIMS m/z 338.15 ([M+H]⁺).

5-Amino-2-chloro-N-(4-oxo-4-((3,3,3-trifluoropropyl)amino)butyl)benzamide(C343)

Isolated as an off-white solid (0.51 g, 17%): mp 121-123° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 8.24 (t, J=6.0 Hz, 1H), 8.02 (t, J=5.2 Hz, 1H),7.04 (d, J=8.8 Hz, 1H), 6.57-6.55 (m, 2H), 5.36 (s, 2H), 3.30-3.24 (m,2H), 3.18-3.13 (m, 2H), 2.50-2.35 (m, 2H), 2.13 (t, J=7.2 Hz, 2H),1.73-1.65 (m, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −63.91; ESIMS m/z 352.41([M+H]⁺).

5-Amino-2-chloro-N-(2-(2,2,2-trifluoroacetamido)ethyl)benzamide (C344)

Isolated as an off-white solid (0.32 g, 18%): mp 157-159° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 9.38-9.35 (m, 1H), 8.38-8.36 (m, 1H), 7.06-7.03 (m,1H), 6.60-6.56 (m, 2H), 5.34 (s, 2H), 3.37-3.28 (m, 4H); ¹⁹F NMR (376MHz, DMSO-d₆) δ −74.47; ESIMS m/z 310.15 ([M+H]⁺).

5-Amino-2-chloro-N-(3-(2,2,2-trifluoroacetamido)propyl)benzamide (C345)

Isolated as an off-white solid (0.80 g, 28%): mp 105-107° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 9.38-9.36 (m, 1H), 8.25 (t, J=5.6 Hz, 1H), 7.04(dd, J=2.0, 7.2 Hz, 1H), 6.59-6.56 (m, 2H), 5.35 (s, 2H), 3.29-3.17 (m,4H), 1.74-1.67 (m, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −74.42; ESIMS m/z324.24 ([M+H]⁺).

5-Amino-2-chloro-N-(4-(2,2,2-trifluoroacetamido)butyl)benzamide (C346)

Isolated as a pale yellow gummy solid (0.98 g, 34%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.44 (t, J=5.6 Hz, 1H), 8.25 (t, J=5.6 Hz, 1H), 7.04 (d,J=8.4 Hz, 1H), 6.57 (d, J=2.8 Hz, 1H), 6.55-6.54 (m, 1H), 5.37 (s, 2H),3.22-3.15 (m, 4H), 1.57-1.45 (m, 4H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−74.36; IR 749.91 cm⁻¹ (C—Cl stretching); ESIMS m/z 338.37 ([M+H]⁺).

5-Amino-2-chloro-N-(2-(2,2,3,3,3-pentafluoropropanamido)ethyl)benzamide(C347)

Isolated as an off-white solid (0.97 g, 46%): mp 150-152° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 9.48 (t, J=5.6 Hz, 1H), 8.32 (t, J=5.2 Hz, 1H),7.05 (d, J=9.2 Hz, 1H), 6.59-6.57 (m, 2H), 5.34 (s, 2H), 3.38-3.29 (m,4H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −82.30, −121.85; ESIMS m/z 360.36([M+H]⁺).

5-Amino-2-chloro-N-(3-(2,2,3,3,3-pentafluoropropanamido)propyl)benzamide(C348)

Isolated as an off-white solid (0.70 g, 21%): mp 118-120° C.; ¹H NMR(400 MHz, DMSO-d₆) δ 9.50 (t, J=5.6 Hz, 1H), 8.27 (t, J=6.0 Hz, 1H),7.05 (dd, J=2.0, 7.6 Hz, 1H), 6.59-6.56 (m, 2H), 5.37 (s, 2H), 3.32-3.25(m, 2H), 3.22-3.16 (m, 2H), 1.74-1.67 (m, 2H); ¹⁹F NMR (376 MHz,DMSO-d₆) δ −82.37, −121.89; ESIMS m/z 374.33 ([M+H]⁺).

5-Amino-2-chloro-N-(4-(2,2,3,3,3-pentafluoropropanamido)butyl)benzamide(C349)

Isolated as a brown gummy solid (0.36 g, 11%): IR 749.81 (C-CIstretching) cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ 9.47-9.46 (m, 1H), 8.21(t, J=5.2 Hz, 1H), 7.04 (d, J=8.0 Hz, 1H), 6.58-6.55 (m, 2H), 5.33 (s,2H), 3.29-3.15 (m, 4H), 1.57-1.44 (m, 4H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ−82.35, −121.76; ESIMS m/z 388 ([M+H]⁺).

Example 95 Preparation of 2-amino-N-(2,2,2-trifluoroethyl)acetamidehydrochloride (C350)

To a stirred solution of tert-butyl(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)carbamate (C362; 3 g, 15.6mmol) in dioxane (20 mL) was added 4 M HCl in dioxane (23 mL, 93.8 mmol)dropwise at 0° C., and the reaction mixture was stirred at roomtemperature for 10 hours. The reaction mixture was concentrated underreduced pressure. The title compound was isolated as an off-white solid(2.4 g), which was used without purification: ¹H NMR (300 MHz, DMSO-d₆)δ 9.17-9.13 (m, 1H), 8.21 (br s, 3H), 4.07-3.95 (m, 2H), 3.67-3.64 (m,2H).

The following compounds were prepared in like manner to the procedureoutlined in Example 95:

3-Amino-N-(2,2,2-trifluoroethyl)propanamide hydrochloride (C351)

Isolated as an off-white solid (2.3 g), which was used withoutpurification: ¹H NMR (300 MHz, DMSO-d₆) δ 8.93 (br s, 1H), 8.21 (br s,3H), 3.97-3.85 (m, 2H), 2.98-2.94 (m, 2H), 2.65-2.60 (m, 2H).

4-Amino-N-(2,2,2-trifluoroethyl)butanamide hydrochloride (C352)

Isolated as an off-white solid (2 g). The product was used in the nextstep without purification and analysis.

2-Amino-N-(3,3,3-trifluoropropyl)acetamide hydrochloride (C353)

Isolated as an off-white solid (2.4 g). The product was used in the nextstep without purification and analysis.

3-Amino-N-(3,3,3-trifluoropropyl)propanamide hydrochloride (C354)

Isolated as an off-white solid (2.7 g). The product was used in the nextstep without purification and analysis.

4-Amino-N-(3,3,3-trifluoropropyl)butanamide hydrochloride (C355)

Isolated as an off-white solid (2.7 g), which was used withoutpurification: ¹H NMR (300 MHz, DMSO-d₆) δ 8.26 (br s, 1H), 8.01 (br s,3H), 3.31-3.24 (m, 2H), 2.78-2.72 (m, 2H), 2.51-2.36 (m, 2H), 2.18 (t,J=7.5 Hz, 2H), 1.82-1.72 (m, 2H).

N-(2-Aminoethyl)-2,2,2-trifluoroacetamide hydrochloride (C356)

Isolated as an off-white solid (2.1 g), which was used withoutpurification: ¹H NMR (300 MHz, DMSO-d₆) δ 9.67 (br s, 1H), 8.24 (br s,3H), 3.50-3.44 (m, 2H), 2.98-2.93 (m, 2H).

N-(3-Aminopropyl)-2,2,2-trifluoroacetamide hydrochloride (C357)

Isolated as an off-white solid (1.7 g). The product was used in the nextstep without purification and analysis.

N-(4-Aminobutyl)-2,2,2-trifluoroacetamide hydrochloride (C358)

Isolated as an off-white solid (3.2 g). The product was used in the nextstep without purification and analysis.

N-(2-Aminoethyl)-2,2,3,3,3-pentafluoropropanamide hydrochloride (C359)

Isolated as an off-white solid (2.9 g), which was used withoutpurification: ¹H NMR (300 MHz, DMSO-d₆) δ 9.78 (br s, 1H), 8.23 (br s,3H), 3.56-3.38 (m, 2H), 2.96-2.94 (m, 2H).

N-(3-Aminopropyl)-2,2,3,3,3-pentafluoropropanamide hydrochloride (C360)

Isolated as an off-white solid (2.9 g): The product was used in the nextstep without purification and analysis.

N-(4-Aminobutyl)-2,2,3,3,3-pentafluoropropanamide hydrochloride (C361)

Isolated as an off-white solid (3.1 g), which was used withoutpurification: ¹H NMR (300 MHz, DMSO-d₆) δ 9.65 (br s, 1H), 8.10 (br s,3H), 3.23-3.21 (m, 2H), 2.78-2.76 (m, 2H), 1.55-1.54 (m, 4H).

Example 96 Preparation of tert-butyl(2-oxo-2-((2,2,2-trifluoroethyl)amino)ethyl)carbamate (C362)

To a solution of (tert-butoxycarbonyl)glycine (3 g, 17.1 mmol) in ethylacetate (25 mL) were added sequentially 2,2,2-trifluoroethan-1-amine(2.55 g, 18.8 mmol), 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane2,4,6-trioxide (50% solution in ethyl acetate; 22 mL, 68.5 mmol), andpyridine (4.4 mL, 54.8 mmol). The reaction mixture was stirred at roomtemperature for 16 hours, then poured into water and extracted withethyl acetate (2×50 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to afford thetitle compound as an off-white solid (3 g), which was used in the nextstep without purification and analysis.

The following compounds were prepared in like manner to the procedureoutlined in Example 96:

tert-Butyl (3-oxo-3-((2,2,2-trifluoroethyl)amino)propyl)carbamate (C363)

Isolated as an off-white solid (2.9 g). The product was used in the nextstep without purification and analysis.

tert-Butyl (4-oxo-4-((2,2,2-trifluoroethyl)amino)butyl)carbamate (C364)

Isolated as an off-white solid (2.9 g). The product was used in the nextstep without purification: ¹H NMR (300 MHz, DMSO-d₆) δ 8.49-8.45 (m,1H), 6.83-6.79 (m, 1H), 3.93-3.81 (m, 2H), 2.89 (dd, J=6.0, 13.2 Hz,2H), 2.16-2.11 (m, 2H), 1.64-1.54 (m, 2H), 1.37 (s, 9H).

tert-Butyl (2-oxo-2-((3,3,3-trifluoropropyl)amino)ethyl)carbamate (C365)

Isolated as an off-white solid (2.8 g). The product was used in the nextstep without purification: ¹H NMR (300 MHz, DMSO-d₆) δ 8.00-7.98 (m,1H), 7.00-6.96 (m, 1H), 3.50-3.25 (m, 4H), 2.50-2.34 (m, 2H), 1.38 (s,9H).

tert-Butyl (3-oxo-3-((3,3,3-trifluoropropyl)amino)propyl)carbamate(C366)

Isolated as an off-white solid (3.2 g). The product was used in the nextstep without purification: ¹H NMR (300 MHz, DMSO-d₆) δ 8.11-8.07 (m,1H), 6.78-6.74 (m, 1H), 3.29-3.22 (m, 2H), 3.14-3.08 (m, 2H), 2.51-2.19(m, 4H), 1.37 (s, 9H).

tert-Butyl (4-oxo-4-((3,3,3-trifluoropropyl)amino)butyl)carbamate (C367)

Isolated as an off-white solid (3.8 g, crude). The product was used inthe next step without purification: ¹H NMR (300 MHz, DMSO-d₆) δ8.05-8.01 (m, 1H), 6.83-6.79 (m, 1H), 3.29-3.22 (m, 2H), 2.91-2.85 (m,2H), 2.45-2.33 (m, 2H), 2.06-1.99 (m, 2H), 1.62-1.52 (m, 2H), 1.37 (s,9H).

Example 97 Preparation of tert-butyl(2-(2,2,2-trifluoroacetamido)ethyl)carbamate (C368)

To a solution of tert-butyl (2-aminoethyl)carbamate (3 g, 18.8 mmol) intetrahydrofuran (25 mL) was added ethyl trifluoroacetate (2.7 g, 18.8mmol), and the reaction mixture was stirred at room temperature for 16hours. The reaction mixture was concentrated under reduced pressure. Thetitle compound was isolated as an off-white solid (2.8 g), which wasused in the next step without any purification: ESIMS m/z 257.40([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 97:

tert-Butyl (3-(2,2,2-trifluoroacetamido)propyl)carbamate (C369)

Isolated as an off-white solid (3.0 g). The product was used in the nextstep without purification: ESIMS m/z 271.40 ([M+H]⁺).

tert-Butyl (4-(2,2,2-trifluoroacetamido)butyl)carbamate (C370)

Isolated as an off-white solid (2.8 g). The product was used in the nextstep without purification: ESIMS m/z 285.41 ([M+H]⁺).

tert-Butyl (2-(2,2,3,3,3-pentafluoropropanamido)ethyl)carbamate (C371)

Isolated as an off-white solid (3.8 g). The product was used in the nextstep without purification: ESIMS m/z 307.37 ([M+H]⁺).

tert-Butyl (3-(2,2,3,3,3-pentafluoropropanamido)propyl)carbamate (C372)

Isolated as an off-white solid (4.3 g). The product was used in the nextstep without purification and analysis.

tert-Butyl (4-(2,2,3,3,3-pentafluoropropanamido)butyl)carbamate (C373)

Isolated as an off-white solid (2.7 g). The product was used in the nextstep without purification and analysis.

Example 98 Preparation of 5-amino-2-chloro-3-fluorobenzoic acid (C196)

To a solution of 2-chloro-3-fluoro-5-nitrobenzoic acid (C206; 0.25 g,1.14 mmol) in ethyl acetate (20 mL) was added 10% palladium on carbon(0.07 g), and the reaction mixture was stirred under a hydrogenatmosphere (20 pounds per square inch (psi)) for 16 hours. The reactionmixture was filtered through a pad of Celite® and washed with ethylacetate, and the filtrate was concentrated under reduced pressure. Theunpurified product was triturated with n-pentane. The title compound wasisolated as an off-white solid (0.18 g, 82%): ¹H NMR (300 MHz, DMSO-d₆)δ 13.24 (br s, 1H), 6.82-6.81 (m, 1H), 6.61 (dd, J=2.7, 12.0 Hz, 1H),5.80 (br s, 2H); ESIMS m/z 189.95 ([M+H]⁺).

Example 99 Preparation ofN-allyl-N-(3-amino-2,6-difluorophenyl)-2,2-difluoroacetamide (C375)

Anhydrous tin chloride (0.62 g, 3.25 mmol) was added portionwise to astirred solution ofN-allyl-N-(2,6-difluoro-3-nitrophenyl)-2,2-difluoroacetamide (C247; 0.19g, 0.65 mmol), in 1:1 methanol-dichloromethane (10 mL) at 5° C. Theresulting yellow solution was stirred at 0-5° C. for 2 hours and for 13hours at 24° C. The reaction mixture was concentrated under vacuum on arotary evaporator. Purification by silica gel flash chromatography using0-60% ethyl acetate in hexanes as eluent afforded the title compound asa gold oil (0.15 g, 83%): ¹H NMR (300 MHz, CDCl₃) δ 6.96-6.82 (m, 2H),6.06-5.62 (m, 2H), 5.23-5.07 (m, 2H), 4.33 (h, J=7.6, 7.0 Hz, 2H), 3.61(s, 2H); ESIMS m/z 263 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 99:

tert-Butyl (3-amino-2,6-difluorophenyl)(prop-2-yn-1-yl)carbamate (C376)

Isolated as a tan solid (0.151 g, 42%): ¹H NMR (400 MHz, CDCl₃) δ6.86-6.59 (m, 2H), 4.47-4.26 (m, 2H), 3.62 (s, 2H), 2.17 (dt, J=18.7,2.5 Hz, 1H), 1.55 (s, 9H); ESIMS m/z 283 ([M+H]⁺).

Example 100 Preparation of tert-butyl(2,6-difluoro-3-nitrophenyl)carbamate (C377)

To a solution oftert-butyl-N-((tert-butoxy)carbonyl)-N-(2,6-difluoro-3-nitrophenyl)carbamate(C190) (2.60 g, 6.60 mmol) in ethyl acetate (66 mL) was addedtrifluoroacetic acid (7.60 g, 66.0 mmol). The reaction mixture wasstirred at room temperature for 5 days. Additional trifluoroacetic acid(6.02 g, 52.3 mmol) was added, and the reaction mixture was stirred foran additional 5 days. The reaction mixture was transferred to aseparatory funnel and washed successively with saturated aqueous sodiumbicarbonate solution until the pH of the organic layer was >3. Theorganic layer was then washed with brine, passed through a phaseseparator to dry and concentrated. Purification by column chromatographyusing 0 to 20% ethyl acetate/hexanes as eluent afforded the titlecompound as a light yellow solid (1.32 g, 73%): ¹H NMR (400 MHz,DMSO-d₆) δ 9.28 (s, 1H), 8.15 (ddd, J=9.5, 8.3, 5.5 Hz, 1H), 7.43 (td,J=9.2, 1.9 Hz, 1H), 1.45 (s, 9H); ¹⁹F NMR (376 MHz, DMSO-d₆) δ −106.41,−121.41; ESIMS m/z 273 ([M−H]⁻).

Example 101 Preparation of2-chloro-N-(2,2-difluoropropyl)-3-fluoro-5-nitrobenzamide (C378)

To a solution of 2-chloro-3-fluoro-5-nitrobenzoic acid (C206; 0.5 g,2.28 mmol) in ethyl acetate (15 mL) were added2,2-difluoropropan-1-amine (0.3 g, 2.28 mmol),2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide [50%solution in ethyl acetate] (2.7 mL, 9.13 mmol), pyridine (0.92 mL, 11.41mmol). The reaction mixture was stirred at room temperature for 16hours. The reaction mixture was diluted with water and extracted withethyl acetate (2×20 mL). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. Purificationby column chromatography (silica gel 100-200 mesh) eluting with 15-20%ethyl acetate in petroleum ether afforded the title compound as anoff-white solid (0.35 g, 60%): ¹H NMR (300 MHz, CDCl₃) δ 8.35-8.33 (m,1H), 8.13 (dd, J=2.7, 7.8 Hz, 1H), 6.44-6.41 (m, 1H), 3.97-3.85 (m, 2H),1.74 (t, J=18.6 Hz, 3H); ESIMS m/z 294.91 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 101:

2-Chloro-N-(2,2-difluorobutyl)-3-fluoro-5-nitrobenzamide (C379)

Isolated as an off-white solid (0.4 g, 56%): ¹H NMR (300 MHz, CDCl₃) δ8.35-8.33 (m, 1H), 8.12 (dd, J=2.4, 8.1 Hz, 1H), 6.48-6.42 (m, 1H),3.97-3.85 (m, 2H), 2.07-1.91 (m, 2H), 1.12 (t, J=7.8 Hz, 3H); ESIMS m/z310.94 ([M+H]⁺).

Ethyl 3-(2-chloro-3-fluoro-5-nitrobenzamido)-2,2-difluoropropanoate(C380)

Isolated as a brown liquid (0.7 g). The product was used in the nextstep without purification: ESIMS m/z 355.15 ([M+H]⁺).

2-Chloro-N-(2,2-difluoro-2-phenylethyl)-3-fluoro-5-nitrobenzamide (C381)

Isolated as an off-white solid (0.4 g, 56%): ¹H NMR (300 MHz, CDCl₃) δ8.26-8.23 (m, 1H), 8.10 (dd, J=2.4, 7.8 Hz, 1H), 7.62-7.48 (m, 5H),6.48-6.41 (m, 1H), 4.23-4.11 (m, 2H); ESIMS m/z 359.15 ([M+H]⁺).

2-Chloro-3-fluoro-5-nitro-N-(2-oxopropyl)benzamide (C382)

Isolated as an off-white solid (0.21 g, 32%): ¹H NMR (400 MHz, CDCl₃) δ8.37-8.34 (m, 1H), 8.11 (dd, J=2.4, 8.4 Hz, 1H), 7.05-7.01 (m, 1H), 4.40(d, J=4.4 Hz, 2H), 2.31 (s, 3H); ESIMS m/z 274.94 ([M+H]⁺).

2-Chloro-3-fluoro-5-nitro-N-(2-oxobutyl)benzamide (C383)

Isolated as a brown liquid (0.35 g). The product was used in the nextstep without purification: ESIMS m/z 289.15 ([M+H]⁺).

2-Chloro-3-fluoro-N-(4-methyl-2-oxopentyl)-5-nitrobenzamide (C384)

Isolated as an off-white solid (0.4 g, 58%): ¹H NMR (300 MHz, CDCl₃) δ8.39-8.36 (m, 1H), 8.12 (dd, J=2.4, 7.8 Hz, 1H), 7.09-7.06 (m, 1H), 4.35(d, J=4.2 Hz, 2H), 2.42 (d, J=6.9 Hz, 2H), 2.27-2.18 (m, 1H), 0.98 (d,J=6.6 Hz, 6H); ESIMS m/z 317.05 ([M+H]⁺).

2-Chloro-3-fluoro-5-nitro-N-(2-oxo-2-phenylethyl)benzamide (C385)

Isolated as an off-white solid (0.4 g, 56%): ¹H NMR (300 MHz, CDCl₃) δ8.43-8.43 (m, 1H), 8.13 (dd, J=2.4, 7.8 Hz, 1H), 8.03 (d, J=7.2 Hz, 2H),7.71-7.65 (m, 1H), 7.58-7.53 (m, 2H), 7.44-7.41 (m, 1H), 5.01 (d, J=4.2Hz, 2H); ESIMS m/z 337.17 ([M+H]⁺).

Example 102 Preparation of2-chloro-N-(2,2-difluoropropyl)-5-nitrobenzamide (C386)

To a solution of 2-chloro-5-nitrobenzoic acid (0.7 g, 3.5 mmol) indichloromethane (10 mL) were added sequentially1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU; 4.0 g, 10.4 mmol),diisopropylethylamine (3 mL, 17.36 mmol) and 2,2-difluoropropan-1-amine(0.5 g, 3.8 mmol). The reaction mixture was stirred at room temperaturefor 16 hours. The reaction mixture was poured into water and wasextracted with dichloromethane (2×20 mL). The organic layer was washedwith brine, dried over Na₂SO₄ and concentrated under reduced pressure.Purification by column chromatography (silica gel 100-200 mesh) elutingwith 40-50% ethyl acetate in petroleum ether afforded the title compoundas an off-white solid (0.9 g, 93%): ¹H NMR (400 MHz, CDCl₃) δ 8.53 (d,J=2.4 Hz, 1H), 8.24 (dd, J=2.4, 8.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H),6.46-6.41 (m, 1H), 3.94-3.86 (m, 2H), 1.73 (t, J=18.8 Hz, 3H); ESIMS m/z279.12 ([M+H]⁺).

The following compounds were prepared in like manner to the procedureoutlined in Example 102:

2-Chloro-N-(2,2-difluorobutyl)-5-nitrobenzamide (C387)

Isolated as an off-white solid (0.4 g, 54%): ¹H NMR (300 MHz, CDCl₃) δ8.53 (d, J=3.0 Hz, 1H), 8.24 (dd, J=3.3, 8.7 Hz, 1H), 7.62 (d, J=8.7 Hz,1H), 6.47-6.44 (m, 1H), 3.97-3.72 (m, 2H), 2.05-1.91 (m, 2H), 1.11 (t,J=7.5 Hz, 3H). Ethyl3-(2-chloro-5-nitrobenzamido)-2,2-difluoropropanoate (C388)

Isolated as an off-white solid (0.7 g, 85%): ¹H NMR (300 MHz, CDCl₃) δ8.52 (d, J=2.4 Hz, 1H), 8.25 (dd, J=2.7, 8.7 Hz, 1H), 7.63 (d, J=9.2 Hz,1H), 6.54-6.52 (m, 1H), 4.38 (q, J=6.9 Hz, 2H), 4.22-4.11 (m, 2H), 1.39(t, J=7.2 Hz, 3H); ESIMS m/z 336.98 ([M+H]⁺).

2-Chloro-N-(2,2-difluoro-2-phenylethyl)-5-nitrobenzamide (C389)

Isolated as an off-white solid (0.68 g, 80%): ¹H NMR (300 MHz, CDCl₃) δ8.42 (d, J=1.2 Hz, 1H), 8.22 (dd, J=1.5, 9.3 Hz, 1H), 7.61-7.47 (m, 6H),6.54-6.51 (m, 1H), 4.32-4.10 (m, 2H); ESIMS m/z 341.14 ([M+H]⁺).

2-Chloro-5-nitro-N-(2-oxopropyl)benzamide (C390)

Isolated as a yellow solid (0.6 g, 50%): ¹H NMR (300 MHz, CDCl₃) δ 8.53(d, J=2.4 Hz, 1H), 8.22 (dd, J=2.1, 8.4 Hz, 1H), 7.61 (d, J=9.2 Hz, 1H),7.09-7.06 (m, 1H), 4.39 (d, J=4.5 Hz, 2H), 2.28 (s, 3H); ESIMS m/z257.01 ([M+H]⁺).

2-Chloro-5-nitro-N-(2-oxobutyl)benzamide (C391)

Isolated as an off-white solid (0.6 g, 38%): ESIMS m/z 271.01 ([M+H]⁺).

2-Chloro-N-(4-methyl-2-oxopentyl)-5-nitrobenzamide (C392)

Isolated as a yellow solid (1.2 g, 81%): ¹H NMR (400 MHz, DMSO-d₆) δ7.06 (d, J=8.4 Hz, 1H), 6.66 (d, J=2.4 Hz, 1H), 6.50 (dd, J=2.8, 8.4 Hz,1H), 3.97 (d, J=6.0 Hz, 2H), 2.36 (d, J=6.8 Hz, 2H) 2.09-2.00 (m, 1H),0.88 (d, J=6.9 Hz, 6H).

2-Chloro-5-nitro-N-(2-oxo-2-phenylethyl)benzamide (C393)

Isolated as an off-white solid (0.6 g, 50%): ESIMS m/z 319.21 ([M+H]⁺).

Example 103 Preparative-SFC separation of5-((1S,3S)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-2-fluoro-N-(4-fluorophenyl)benzamide(F1373) and5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-2-fluoro-N-(4-fluorophenyl)benzamide(F1374)

Racemic5-((trans)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-2-fluoro-N-(4-fluorophenyl)benzamide(U.S. Patent Application Publication US20160304522A1 (F129)) wasseparated by preparative-SFC utilizing the following conditions: ICcolumn (20 mm×250 mm), 5 μm; 35/65 MeOH (0.2% diethylamine)/CO₂, 40g/min to give5-((1S,3S)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-2-fluoro-N-(4-fluorophenyl)benzamide(F1373) (2^(nd) eluting enantiomer, 100% ee) and5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-2-fluoro-N-(4-fluorophenyl)benzamide(F1374) (1^(st) eluting enantiomer, 98.5% ee).

Example 104 Preparative-HPLC separation of5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-2-fluorobenzamide(F1375) and5-((1S,3S)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-2-fluorobenzamide(F1376)

Racemic5-((trans)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-2-fluorobenzamide(U.S. Patent Application Publication US20160304522A1 (F61)) wasseparated by preparative HPLC utilizing the following conditions: OJ-Hcolumn (20 mm×250 mm), 5 μm; 50/50 isopropanol (0.2%diethylamine)/hexane, 4.0 mL/min to give5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-2-fluorobenzamide(F1375) (1^(st) eluting enantiomer, 96.2% ee) and5-((1S,3S)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4-difluorophenyl)-2-fluorobenzamide(F1376) (2^(nd) eluting enantiomer, 96.0% ee).

Example 105 Preparative-SFC separation of2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4,6-trifluorophenyl)benzamide(F1377) and2-chloro-5-((1S,3S)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4,6-trifluorophenyl)benzamide(F1378)

Racemic2-Chloro-5-((trans)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4,6-trifluorophenyl)benzamide(U.S. Patent Application Publication US20160304522A1 (F24)) wasseparated by preparative-SFC utilizing the following conditions: ICcolumn (20 mm×250 mm), 5 μm; 35/65 MeOH (0.2% diethylamine)/CO₂, 40g/min to give2-chloro-5-((1R,3R)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4,6-trifluorophenyl)benzamide(F1377) (1^(st) eluting enantiomer, 100% ee) and2-chloro-5-((15,3S)-2,2-dichloro-3-(3,5-dichlorophenyl)cyclopropane-1-carboxamido)-N-(2,4,6-trifluorophenyl)benzamide(F1378) (2^(nd) eluting enantiomer, 100% ee).

It is recognized that some reagents and reaction conditions may not becompatible with certain functionalities that may be present in certainmolecules of Formula One or certain molecules used in the preparation ofcertain molecules of Formula One. In such cases, it may be necessary toemploy standard protection and deprotection protocols comprehensivelyreported in the literature and well known to a person skilled in theart. In addition, in some cases it may be necessary to perform furtherroutine synthetic steps not described herein to complete the synthesisof desired molecules. A person skilled in the art will also recognizethat it may be possible to achieve the synthesis of desired molecules byperforming some of the steps of the synthetic routes in a differentorder to that described. A person skilled in the art will also recognizethat it may be possible to perform standard functional groupinterconversions or substitution reactions on desired molecules tointroduce or modify substituents.

Biological Assays

The following bioassays against Beet Armyworm (Spodoptera exigua),Cabbage Looper (Trichoplusia ni), and Yellow Fever Mosquito (Aedesaegypti), are included herein due to the damage they inflict.Furthermore, the Beet Armyworm and Cabbage Looper are two good indicatorspecies for a broad range of chewing pests. Additionally, the GreenPeach Aphid is a good indicator species for a broad range of sap-feedingpests. The results with these four indicator species along with theYellow Fever Mosquito show the broad usefulness of the molecules ofFormula One in controlling pests in Phyla Arthropoda, Mollusca, andNematoda (Drewes et al.)

Example A Bioassays on Beet Armyworm (Spodoptera exigua, LAPHEG) (“BAW”)and Cabbage Looper (Trichoplusia ni, TRIPNI) (“CL”)

Beet armyworm is a serious pest of economic concern for alfalfa,asparagus, beets, citrus, corn, cotton, onions, peas, peppers, potatoes,soybeans, sugar beets, sunflowers, tobacco, and tomatoes, among othercrops. It is native to Southeast Asia but is now found in Africa,Australia, Japan, North America, and Southern Europe. The larvae mayfeed in large swarms causing devastating crop losses. It is known to beresistant to several pesticides.

Cabbage looper is a serious pest found throughout the world. It attacksalfalfa, beans, beets, broccoli, Brussel sprouts, cabbage, cantaloupe,cauliflower, celery, collards, cotton, cucumbers, eggplant, kale,lettuce, melons, mustard, parsley, peas, peppers, potatoes, soybeans,spinach, squash, tomatoes, turnips, and watermelons, among other crops.This species is very destructive to plants due to its voraciousappetite. The larvae consume three times their weight in food daily. Thefeeding sites are marked by large accumulations of sticky, wet, fecalmaterial, which may contribute to higher disease pressure therebycausing secondary problems on the plants in the site. It is known to beresistant to several pesticides.

Consequently, because of the above factors control of these pests isimportant. Furthermore, molecules that control these pests (BAW and CL),which are known as chewing pests, will be useful in controlling otherpests that chew on plants.

Certain molecules disclosed in this document were tested against BAW andCL using procedures described in the following examples. In thereporting of the results, the “BAW & CL Rating Table” was used (SeeTable Section).

Bioassays on BAW

Bioassays on BAW were conducted using a 128-well diet tray assay. One tofive second instar BAW larvae were placed in each well (3 mL) of thediet tray that had been previously filled with 1 mL of artificial dietto which 50 μg/cm² of the test molecule (dissolved in 50 μL of 90:10acetone-water mixture) had been applied (to each of eight wells) andthen allowed to dry. Trays were covered with a clear self-adhesivecover, vented to allow gas exchange, and held at 25° C., 14:10light-dark for five to seven days. Percent mortality was recorded forthe larvae in each well; activity in the eight wells was then averaged.The results are indicated in the table entitled “Table ABC: BiologicalResults” (See Table Section).

Bioassays on CL

Bioassays on CL were conducted using a 128-well diet tray assay. One tofive second instar CL larvae were placed in each well (3 mL) of the diettray that had been previously filled with 1 mL of artificial diet towhich 50 μg/cm² of the test molecule (dissolved in 50 μL of 90:10acetone-water mixture) had been applied (to each of eight wells) andthen allowed to dry. Trays were covered with a clear self-adhesivecover, vented to allow gas exchange, and held at 25° C., 14:10light-dark for five to seven days. Percent mortality was recorded forthe larvae in each well; activity in the eight wells was then averaged.The results are indicated in the table entitled “Table ABC: BiologicalResults” (See Table Section).

Example B Bioassays on Green Peach Aphid (Myzus persicae, MYZUPE)(“GPA”)

GPA is the most significant aphid pest of peach trees, causing decreasedgrowth, shriveling of the leaves, and the death of various tissues. Itis also hazardous because it acts as a vector for the transport of plantviruses, such as potato virus Y and potato leafroll virus to members ofthe nightshade/potato family Solanaceae, and various mosaic viruses tomany other food crops. GPA attacks such plants as broccoli, burdock,cabbage, carrot, cauliflower, daikon, eggplant, green beans, lettuce,macadamia, papaya, peppers, sweet potatoes, tomatoes, watercress, andzucchini, among other crops. GPA also attacks many ornamental crops suchas carnation, chrysanthemum, flowering white cabbage, poinsettia, androses. GPA has developed resistance to many pesticides. Currently, it isa pest that has the third largest number of reported cases of insectresistance (Sparks et al.). Consequently, because of the above factorscontrol of this pest is important. Furthermore, molecules that controlthis pest (GPA), which is known as a sap-feeding pest, are useful incontrolling other pests that feed on the sap from plants.

Certain molecules disclosed in this document were tested against GPAusing procedures described in the following example. In the reporting ofthe results, the “GPA & YFM Rating Table” was used (See Table Section).

Cabbage seedlings grown in 3-inch pots, with 2-3 small (3-5 cm) trueleaves, were used as test substrate. The seedlings were infested with20-50 GPA (wingless adult and nymph stages) one day prior to chemicalapplication. Four pots with individual seedlings were used for eachtreatment. Test molecules (2 mg) were dissolved in 2 mL ofacetone/methanol (1:1) solvent, forming stock solutions of 1000 ppm testmolecule. The stock solutions were diluted 5× with 0.025% Tween 20 inwater to obtain the solution at 200 ppm test molecule. A hand-heldaspirator-type sprayer was used for spraying a solution to both sides ofcabbage leaves until runoff. Reference plants (solvent check) weresprayed with the diluent only containing 20% by volume ofacetone/methanol (1:1) solvent. Treated plants were held in a holdingroom for three days at approximately 25° C. and ambient relativehumidity (RH) prior to grading. Evaluation was conducted by counting thenumber of live aphids per plant under a microscope. Percent control wasmeasured using Abbott's correction formula (W. S. Abbott, “A Method ofComputing the Effectiveness of an Insecticide” 3. Econ. Entomol. 18(1925), pp. 265-267) as follows. Corrected % Control=100*(X−Y)/X whereX=No. of live aphids on solvent check plants and Y=No. of live aphids ontreated plants. The results are indicated in the table entitled “TableABC: Biological Results” (See Table Section).

Example C Bioassays on Yellow Fever Mosquito (Aedes aegypti, AEDSAE)(“YFM”)

YFM prefers to feed on humans during the daytime and is most frequentlyfound in or near human habitations. YFM is a vector for transmittingseveral diseases. It is a mosquito that can spread the dengue fever andyellow fever viruses. Yellow fever is the second most dangerousmosquito-borne disease after malaria. Yellow fever is an acute viralhemorrhagic disease and up to 50% of severely affected persons withouttreatment will die from yellow fever. There are an estimated 200,000cases of yellow fever, causing 30,000 deaths worldwide each year. Denguefever is a nasty, viral disease; it is sometimes called “breakbonefever” or “break-heart fever” because of the intense pain it canproduce. Dengue fever kills about 20,000 people annually. Consequently,because of the above factors control of this pest is important.Furthermore, molecules that control this pest (YFM), which is known as asucking pest, are useful in controlling other pests that cause human andanimal suffering.

Certain molecules disclosed in this document were tested against YFMusing procedures described in the following paragraph. In the reportingof the results, the “GPA & YFM Rating Table” was used (See TableSection).

Master plates containing 400 pg of a molecule dissolved in 100 μL ofdimethyl sulfoxide (DMSO) (equivalent to a 4000 ppm solution) are used.A master plate of assembled molecules contains 15 μL per well. To thisplate, 135 μL of a 90:10 water/acetone mixture is added to each well. Arobot (Biomek® NXP Laboratory Automation Workstation) is programmed todispense 15 μL aspirations from the master plate into an empty 96-wellshallow plate (“daughter” plate). There are 6 reps (“daughter” plates)created per master. The created “daughter” plates are then immediatelyinfested with YFM larvae.

The day before plates are to be treated, mosquito eggs are placed inMillipore water containing liver powder to begin hatching (4 g into 400mL). After the “daughter” plates are created using the robot, they areinfested with 220 μL of the liver powder/larval mosquito mixture (about1 day-old larvae). After plates are infested with mosquito larvae, anon-evaporative lid is used to cover the plate to reduce drying. Platesare held at room temperature for 3 days prior to grading. After 3 days,each well is observed and scored based on mortality. The results areindicated in the table entitled “Table ABC: Biological Results” (SeeTable Section).

Agriculturally Acceptable Acid Addition Salts, Salt Derivatives,Solvates, Ester Derivatives, Polymorphs, Isotopes, and Radionuclides

Molecules of Formula One may be formulated into agriculturallyacceptable acid addition salts. By way of a non-limiting example, anamine function can form salts with hydrochloric, hydrobromic, sulfuric,phosphoric, acetic, benzoic, citric, malonic, salicylic, malic, fumaric,oxalic, succinic, tartaric, lactic, gluconic, ascorbic, maleic,aspartic, benzenesulfonic, methanesulfonic, ethanesulfonic,hydroxyl-methanesulfonic, and hydroxyethanesulfonic acids. Additionally,by way of a non-limiting example, an acid function can form saltsincluding those derived from alkali or alkaline earth metals and thosederived from ammonia and amines. Examples of preferred cations includesodium, potassium, and magnesium.

Molecules of Formula One may be formulated into salt derivatives. By wayof a non-limiting example, a salt derivative may be prepared bycontacting a free base with a sufficient amount of the desired acid toproduce a salt. A free base may be regenerated by treating the salt witha suitable dilute aqueous base solution such as dilute aqueous sodiumhydroxide, potassium carbonate, ammonia, and sodium bicarbonate. As anexample, in many cases, a pesticide, such as 2,4-D, is made morewater-soluble by converting it to its dimethylamine salt.

Molecules of Formula One may be formulated into stable complexes with asolvent, such that the complex remains intact after the non-complexedsolvent is removed. These complexes are often referred to as “solvates.”However, it is particularly desirable to form stable hydrates with wateras the solvent.

Molecules of Formula One containing an acid functionality may be madeinto ester derivatives. These ester derivatives can then be applied inthe same manner as the molecules disclosed in this document are applied.

Molecules of Formula One may be made as various crystal polymorphs.Polymorphism is important in the development of agrochemicals sincedifferent crystal polymorphs or structures of the same molecule can havevastly different physical properties and biological performances.

Molecules of Formula One may be made with different isotopes. Ofparticular importance are molecules having ²H (also known as deuterium)or ³H (also known as tritium) in place of ¹H. Molecules of Formula Onemay be made with different radionuclides. Of particular importance aremolecules having ¹⁴C (also known as radiocarbon). Molecules of FormulaOne having deuterium, tritium, or ¹⁴C may be used in biological studiesallowing tracing in chemical and physiological processes and half-lifestudies, as well as, MoA studies.

Combinations

In another embodiment of this invention, molecules of Formula One may beused in combination (such as, in a compositional mixture, or asimultaneous or sequential application) with one or more activeingredients.

In another embodiment of this invention, molecules of Formula One may beused in combination (such as, in a compositional mixture, or asimultaneous or sequential application) with one or more activeingredients each having a MoA that is the same as, similar to, but morelikely—different from, the MoA of the molecules of Formula One.

In another embodiment, molecules of Formula One may be used incombination (such as, in a compositional mixture, or a simultaneous orsequential application) with one or more molecules having acaricidal,algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal,molluscicidal, nematicidal, rodenticidal, and/or virucidal properties.

In another embodiment, the molecules of Formula One may be used incombination (such as, in a compositional mixture, or a simultaneous orsequential application) with one or more molecules that areantifeedants, bird repellents, chemosterilants, herbicide safeners,insect attractants, insect repellents, mammal repellents, matingdisrupters, plant activators, plant growth regulators, and/orsynergists.

In another embodiment, molecules of Formula One may also be used incombination (such as in a compositional mixture, or a simultaneous orsequential application) with one or more biopesticides.

In another embodiment, in a pesticidal composition combinations of amolecule of Formula One and an active ingredient may be used in a widevariety of weight ratios. For example, in a two-component mixture, theweight ratio of a molecule of Formula One to an active ingredient, theweight ratios in Table B may be used. However, in general, weight ratiosless than about 10:1 to about 1:10 are preferred. It is also preferredsometimes to use a three, four, five, six, seven, or more, componentmixture comprising a molecule of Formula One and an additional two ormore active ingredients.

Weight ratios of a molecule of Formula One to an active ingredient mayalso be depicted as X: Y; wherein X is the parts by weight of a moleculeof Formula One and Y is the parts by weight of active ingredient. Thenumerical range of the parts by weight for X is 0<X≤100 and the parts byweight for Y is 0<Y≤100 and is shown graphically in TABLE C. By way ofnon-limiting example, the weight ratio of a molecule of Formula One toan active ingredient may be 20:1.

Ranges of weight ratios of a molecule of Formula One to an activeingredient may be depicted as X₁:Y₁ to X₂:Y₂, wherein X and Y aredefined as above.

In one embodiment, the range of weight ratios may be X₁:Y₁ to X₂:Y₂,wherein X₁>Y₁ and X₂<Y₂. By way of non-limiting example, the range of aweight ratio of a molecule of Formula One to an active ingredient may bebetween 3:1 and 1:3, inclusive of the endpoints.

In another embodiment, the range of weight ratios may be X₁:Y₁ to X₂:Y₂,wherein X₁>Y₁ and X₂>Y₂. By way of non-limiting example, the range ofweight ratio of a molecule of Formula One to an active ingredient may bebetween 15:1 and 3:1, inclusive of the endpoints.

In another embodiment, the range of weight ratios may be X₁:Y₁ to X₂:Y₂,wherein X₁<Y₁ and X₂<Y₂. By way of non-limiting example, the range ofweight ratios of a molecule of Formula One to an active ingredient maybe between about 1:3 and about 1:20, inclusive of the endpoints.

Formulations

A pesticide is many times not suitable for application in its pure form.It is usually necessary to add other substances so that the pesticidemay be used at the required concentration and in an appropriate form,permitting ease of application, handling, transportation, storage, andmaximum pesticide activity. Thus, pesticides are formulated into, forexample, baits, concentrated emulsions, dusts, emulsifiableconcentrates, fumigants, gels, granules, microencapsulations, seedtreatments, suspension concentrates, suspoemulsions, tablets, watersoluble liquids, water dispersible granules or dry flowables, wettablepowders, and ultra-low volume solutions.

Pesticides are applied most often as aqueous suspensions or emulsionsprepared from concentrated formulations of such pesticides. Suchwater-soluble, water-suspendable, or emulsifiable formulations areeither solids, usually known as wettable powders, water dispersiblegranules, liquids usually known as emulsifiable concentrates, or aqueoussuspensions. Wettable powders, which may be compacted to form waterdispersible granules, comprise an intimate mixture of the pesticide, acarrier, and surfactants. The concentration of the pesticide is usuallyfrom about 10% to about 90% by weight. The carrier is usually selectedfrom among the attapulgite clays, the montmorillonite clays, thediatomaceous earths, or the purified silicates. Effective surfactants,comprising from about 0.5% to about 10% of the wettable powder, arefound among sulfonated lignins, condensed naphthalenesulfonates,naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates, andnon-ionic surfactants such as ethylene oxide adducts of alkyl phenols.

Emulsifiable concentrates of pesticides comprise a convenientconcentration of a pesticide, such as from about 50 to about 500 gramsper liter of liquid dissolved in a carrier that is either a watermiscible solvent or a mixture of water-immiscible organic solvent andemulsifiers. Useful organic solvents include aromatics, especiallyxylenes and petroleum fractions, especially the high-boilingnaphthalenic and olefinic portions of petroleum such as heavy aromaticnaphtha. Other organic solvents may also be used, such as the terpenicsolvents including rosin derivatives, aliphatic ketones such ascyclohexanone, and complex alcohols such as 2-ethoxyethanol. Suitableemulsifiers for emulsifiable concentrates are selected from conventionalanionic and non-ionic surfactants.

Aqueous suspensions comprise suspensions of water-insoluble pesticidesdispersed in an aqueous carrier at a concentration in the range fromabout 5% to about 50% by weight. Suspensions are prepared by finelygrinding the pesticide and vigorously mixing it into a carrier comprisedof water and surfactants. Ingredients, such as inorganic salts andsynthetic or natural gums may, also be added to increase the density andviscosity of the aqueous carrier. It is often most effective to grindand mix the pesticide at the same time by preparing the aqueous mixtureand homogenizing it in an implement such as a sand mill, ball mill, orpiston-type homogenizer. The pesticide in suspension might bemicroencapsulated in plastic polymer.

Oil dispersions (OD) comprise suspensions of organic solvent-insolublepesticides finely dispersed in a mixture of organic solvent andemulsifiers at a concentration in the range from about 2% to about 50%by weight. One or more pesticide might be dissolved in the organicsolvent. Useful organic solvents include aromatics, especially xylenesand petroleum fractions, especially the high-boiling naphthalenic andolefinic portions of petroleum such as heavy aromatic naphtha. Othersolvents may include vegetable oils, seed oils, and esters of vegetableand seed oils. Suitable emulsifiers for oil dispersions are selectedfrom conventional anionic and non-ionic surfactants. Thickeners orgelling agents are added in the formulation of oil dispersions to modifythe rheology or flow properties of the liquid and to prevent separationand settling of the dispersed particles or droplets.

Pesticides may also be applied as granular compositions that areparticularly useful for applications to the soil. Granular compositionsusually contain from about 0.5% to about 10% by weight of the pesticide,dispersed in a carrier that comprises clay or a similar substance. Suchcompositions are usually prepared by dissolving the pesticide in asuitable solvent and applying it to a granular carrier, which has beenpre-formed to the appropriate particle size, in the range of from about0.5 mm to about 3 mm. Such compositions may also be formulated by makinga dough or paste of the carrier and molecule, and then crushing anddrying to obtain the desired granular particle size. Another form ofgranules is a water emulsifiable granule (EG). It is a formulationconsisting of granules to be applied as a conventional oil-in-wateremulsion of the active ingredient(s), either solubilized or diluted inan organic solvent, after disintegration and dissolution in water. Wateremulsifiable granules comprise one or several active ingredient(s),either solubilized or diluted in a suitable organic solvent that is(are) absorbed in a water soluble polymeric shell or some other type ofsoluble or insoluble matrix.

Dusts containing a pesticide are prepared by intimately mixing thepesticide in powdered form with a suitable dusty agricultural carrier,such as kaolin clay, ground volcanic rock, and the like. Dusts cansuitably contain from about 1% to about 10% of the pesticide. Dusts maybe applied as a seed dressing or as a foliage application with a dustblower machine.

It is equally practical to apply a pesticide in the form of a solutionin an appropriate organic solvent, usually petroleum oil, such as thespray oils, which are widely used in agricultural chemistry.

Pesticides can also be applied in the form of an aerosol composition. Insuch compositions, the pesticide is dissolved or dispersed in a carrier,which is a pressure-generating propellant mixture. The aerosolcomposition is packaged in a container from which the mixture isdispensed through an atomizing valve.

Pesticide baits are formed when the pesticide is mixed with food or anattractant or both. When the pests eat the bait, they also consume thepesticide. Baits may take the form of granules, gels, flowable powders,liquids, or solids. Baits may be used in pest harborages.

Fumigants are pesticides that have a relatively high vapor pressure andhence can exist as a gas in sufficient concentrations to kill pests insoil or enclosed spaces. The toxicity of the fumigant is proportional toits concentration and the exposure time. They are characterized by agood capacity for diffusion and act by penetrating the pest'srespiratory system or being absorbed through the pest's cuticle.Fumigants are applied to control stored product pests under gas proofsheets, in gas sealed rooms or buildings, or in special chambers.

Pesticides may be microencapsulated by suspending the pesticideparticles or droplets in plastic polymers of various types. By altering,the chemistry of the polymer or by changing factors in the processing,microcapsules may be formed of various sizes, solubility, wallthicknesses, and degrees of penetrability. These factors govern thespeed with which the active ingredient within is released, which inturn, affects the residual performance, speed of action, and odor of theproduct. The microcapsules might be formulated as suspensionconcentrates or water dispersible granules.

Oil solution concentrates are made by dissolving pesticide in a solventthat will hold the pesticide in solution. Oil solutions of a pesticideusually provide faster knockdown and kill of pests than otherformulations due to the solvents themselves having pesticidal action andthe dissolution of the waxy covering of the integument increasing thespeed of uptake of the pesticide. Other advantages of oil solutionsinclude better storage stability, better penetration of crevices, andbetter adhesion to greasy surfaces.

Another embodiment is an oil-in-water emulsion, wherein the emulsioncomprises oily globules which are each provided with a lamellar liquidcrystal coating and are dispersed in an aqueous phase, wherein each oilyglobule comprises at least one molecule which is agriculturally active,and is individually coated with a monolamellar or oligolamellar layercomprising: (1) at least one non-ionic lipophilic surface-active agent,(2) at least one non-ionic hydrophilic surface-active agent, and (3) atleast one ionic surface-active agent, wherein the globules having a meanparticle diameter of less than 800 nanometers.

Other Formulation Components

Generally, when the molecules disclosed in Formula One are used in aformulation, such formulation can also contain other components. Thesecomponents include, but are not limited to, (this is a non-exhaustiveand non-mutually exclusive list) wetters, spreaders, stickers,penetrants, buffers, sequestering agents, drift reduction agents,compatibility agents, anti-foam agents, cleaning agents, andemulsifiers. A few components are described forthwith.

A wetting agent is a substance that when added to a liquid increases thespreading or penetration power of the liquid by reducing the interfacialtension between the liquid and the surface on which it is spreading.Wetting agents are used for two main functions in agrochemicalformulations: during processing and manufacture to increase the rate ofwetting of powders in water to make concentrates for soluble liquids orsuspension concentrates; and during mixing of a product with water in aspray tank to reduce the wetting time of wettable powders and to improvethe penetration of water into water-dispersible granules. Examples ofwetting agents used in wettable powder, suspension concentrate, andwater-dispersible granule formulations are: sodium lauryl sulfate,sodium dioctyl sulfosuccinate, alkyl phenol ethoxylates, and aliphaticalcohol ethoxylates.

A dispersing agent is a substance that adsorbs onto the surface ofparticles, helps to preserve the state of dispersion of the particles,and prevents them from reaggregating. Dispersing agents are added toagrochemical formulations to facilitate dispersion and suspension duringmanufacture, and to ensure the particles redisperse into water in aspray tank. They are widely used in wettable powders, suspensionconcentrates, and water-dispersible granules. Surfactants that are usedas dispersing agents have the ability to adsorb strongly onto a particlesurface and provide a charged or steric barrier to reaggregation ofparticles. The most commonly used surfactants are anionic, non-ionic, ormixtures of the two types. For wettable powder formulations, the mostcommon dispersing agents are sodium lignosulfonates. For suspensionconcentrates, very good adsorption and stabilization are obtained usingpolyelectrolytes, such assodium-naphthalene-sulfonate-formaldehyde-condensates. Tristyrylphenolethoxylate phosphate esters are also used. Non-ionics such asalkylarylethylene oxide condensates and EO-PO block copolymers aresometimes combined with anionics as dispersing agents for suspensionconcentrates. In recent years, new types of very high molecular weightpolymeric surfactants have been developed as dispersing agents. Thesehave very long hydrophobic ‘backbones’ and a large number of ethyleneoxide chains forming the ‘teeth’ of a ‘comb’ surfactant. These highmolecular weight polymers can give very good long-term stability tosuspension concentrates because the hydrophobic backbones have manyanchoring points onto the particle surfaces. Examples of dispersingagents used in agrochemical formulations are: sodium lignosulfonates,sodium naphthalene sulfonate formaldehyde condensates,tristyrylphenol-ethoxylate-phosphate-esters, aliphatic alcoholethoxylates, alkyl ethoxylates, EO-PO block copolymers, and graftcopolymers.

An emulsifying agent is a substance that stabilizes a suspension ofdroplets of one liquid phase in another liquid phase. Without theemulsifying agent, the two liquids would separate into two immiscibleliquid phases. The most commonly used emulsifier blends contain analkylphenol or an aliphatic alcohol with twelve or more ethylene oxideunits and the oil-soluble calcium salt of dodecylbenzenesulfonic acid. Arange of hydrophile-lipophile balance (“HLB”) values from about 8 toabout 18 will normally provide good stable emulsions. Emulsion stabilitycan sometimes be improved by the addition of a small amount of an EO-POblock copolymer surfactant.

A solubilizing agent is a surfactant that will form micelles in water atconcentrations above the critical micelle concentration. The micellesare then able to dissolve or solubilize water-insoluble materials insidethe hydrophobic part of the micelle. The types of surfactants usuallyused for solubilization are non-ionics, sorbitan monooleates, sorbitanmonooleate ethoxylates, and methyl oleate esters.

Surfactants are sometimes used, either alone or with other additivessuch as mineral or vegetable oils as adjuvants to spray-tank mixes toimprove the biological performance of the pesticide on the target. Thetypes of surfactants used for bioenhancement depend generally on thenature and mode of action of the pesticide. However, they are oftennon-ionics such as: alkyl ethoxylates, linear aliphatic alcoholethoxylates, and aliphatic amine ethoxylates.

A carrier or diluent in an agricultural formulation is a material addedto the pesticide to give a product of the required strength. Carriersare usually materials with high absorptive capacities, while diluentsare usually materials with low absorptive capacities. Carriers anddiluents are used in the formulation of dusts, wettable powders,granules, and water-dispersible granules.

Organic solvents are used mainly in the formulation of emulsifiableconcentrates, oil-in-water emulsions, suspoemulsions, oil dispersions,and ultra-low volume formulations, and to a lesser extent, granularformulations. Sometimes mixtures of solvents are used. The first maingroups of solvents are aliphatic paraffinic oils such as kerosene orrefined paraffins. The second main group (and the most common) comprisesthe aromatic solvents such as xylene and higher molecular weightfractions of C9 and C10 aromatic solvents. Chlorinated hydrocarbons areuseful as cosolvents to prevent crystallization of pesticides when theformulation is emulsified into water. Alcohols are sometimes used ascosolvents to increase solvent power. Other solvents may includevegetable oils, seed oils, and esters of vegetable and seed oils.

Thickeners or gelling agents are used mainly in the formulation ofsuspension concentrates, oil dispersions, emulsions and suspoemulsionsto modify the rheology or flow properties of the liquid and to preventseparation and settling of the dispersed particles or droplets.Thickening, gelling, and anti-settling agents generally fall into twocategories, namely water-insoluble particulates and water-solublepolymers. It is possible to produce suspension concentrate and oildispersion formulations using clays and silicas. Examples of these typesof materials, include, but are not limited to, montmorillonite,bentonite, magnesium aluminum silicate, and attapulgite. Water-solublepolysaccharides in water based suspension concentrates have been used asthickening-gelling agents for many years. The types of polysaccharidesmost commonly used are natural extracts of seeds and seaweeds or aresynthetic derivatives of cellulose. Examples of these types of materialsinclude, but are not limited to, guar gum, locust bean gum, carrageenam,alginates, methyl cellulose, sodium carboxymethyl cellulose (SCMC), andhydroxyethyl cellulose (HEC). Other types of anti-settling agents arebased on modified starches, polyacrylates, polyvinyl alcohol, andpolyethylene oxide. Another good anti-settling agent is xanthan gum.

Microorganisms can cause spoilage of formulated products. Therefore,preservation agents are used to eliminate or reduce their effect.Examples of such agents include, but are not limited to: propionic acidand its sodium salt, sorbic acid and its sodium or potassium salts,benzoic acid and its sodium salt, p-hydroxybenzoic acid sodium salt,methyl p-hydroxybenzoate, and 1,2-benzisothiazolin-3-one (BIT).

The presence of surfactants often causes water-based formulations tofoam during mixing operations in production and in application through aspray tank. In order to reduce the tendency to foam, anti-foam agentsare often added either during the production stage or before fillinginto bottles. Generally, there are two types of anti-foam agents, namelysilicones and non-silicones. Silicones are usually aqueous emulsions ofdimethyl polysiloxane, while the non-silicone anti-foam agents arewater-insoluble oils, such as octanol and nonanol, or silica. In bothcases, the function of the anti-foam agent is to displace the surfactantfrom the air-water interface.

“Green” agents (e.g., adjuvants, surfactants, solvents) can reduce theoverall environmental footprint of crop protection formulations. Greenagents are biodegradable and generally derived from natural and/orsustainable sources, e.g. plant and animal sources. Specific examplesare: vegetable oils, seed oils, and esters thereof, also alkoxylatedalkyl polyglucosides.

Applications

Molecules of Formula One may be applied to any locus. Particular loci toapply such molecules include loci where alfalfa, almonds, apples,barley, beans, canola, corn, cotton, crucifers, flowers, fodder species(Rye Grass, Sudan Grass, Tall Fescue, Kentucky Blue Grass, and Clover),fruits, lettuce, oats, oil seed crops, oranges, peanuts, pears, peppers,potatoes, rice, sorghum, soybeans, strawberries, sugarcane, sugarbeets,sunflowers, tobacco, tomatoes, wheat (for example, Hard Red WinterWheat, Soft Red Winter Wheat, White Winter Wheat, Hard Red Spring Wheat,and Durum Spring Wheat), and other valuable crops are growing or theseeds thereof are going to be planted.

Molecules of Formula One may also be applied where plants, such ascrops, are growing and where there are low levels (even no actualpresence) of pests that can commercially damage such plants. Applyingsuch molecules in such locus is to benefit the plants being grown insuch locus. Such benefits, may include, but are not limited to: helpingthe plant grow a better root system; helping the plant better withstandstressful growing conditions; improving the health of a plant; improvingthe yield of a plant (e.g. increased biomass and/or increased content ofvaluable ingredients); improving the vigor of a plant (e.g. improvedplant growth and/or greener leaves); improving the quality of a plant(e.g. improved content or composition of certain ingredients); andimproving the tolerance to abiotic and/or biotic stress of the plant.

Molecules of Formula One may be applied with ammonium sulfate whengrowing various plants as this may provide additional benefits.

Molecules of Formula One may be applied on, in, or around plantsgenetically modified to express specialized traits, such as Bacillusthuringiensis (for example, Cry1Ab, Cry1Ac, Cry1Fa, Cry1A.105, Cry2Ab,Vip3A, mCry3A, Cry3Ab, Cry3Bb, Cry34Ab1/Cry35Ab1), other insecticidaltoxins, or those expressing herbicide tolerance, or those with “stacked”foreign genes expressing insecticidal toxins, herbicide tolerance,nutrition-enhancement, or any other beneficial traits.

Molecules of Formula One may be applied to the foliar and/or fruitingportions of plants to control pests. Either such molecules will come indirect contact with the pest, or the pest will consume such moleculeswhen eating the plant or while extracting sap or other nutrients fromthe plant.

Molecules of Formula One may also be applied to the soil, and whenapplied in this manner, root and stem feeding pests may be controlled.The roots may absorb such molecules thereby taking it up into the foliarportions of the plant to control above ground chewing and sap feedingpests.

Systemic movement of pesticides in plants may be utilized to controlpests on one portion of the plant by applying (for example by spraying alocus) a molecule of Formula One to a different portion of the plant.For example, control of foliar-feeding insects may be achieved by dripirrigation or furrow application, by treating the soil with for examplepre- or post-planting soil drench, or by treating the seeds of a plantbefore planting.

Molecules of Formula One may be used with baits. Generally, with baits,the baits are placed in the ground where, for example, termites can comeinto contact with, and/or be attracted to, the bait. Baits can also beapplied to a surface of a building, (horizontal, vertical, or slantsurface) where, for example, ants, termites, cockroaches, and flies, cancome into contact with, and/or be attracted to, the bait.

Molecules of Formula One may be encapsulated inside, or placed on thesurface of a capsule. The size of the capsules can range from nanometersize (about 100-900 nanometers in diameter) to micrometer size (about10-900 microns in diameter).

Molecules of Formula One may be applied to eggs of pests. Because of theunique ability of the eggs of some pests to resist certain pesticides,repeated applications of such molecules may be desirable to controlnewly emerged larvae.

Molecules of Formula One may be applied as seed treatments. Seedtreatments may be applied to all types of seeds, including those fromwhich plants genetically modified to express specialized traits willgerminate. Representative examples include those expressing proteinstoxic to invertebrate pests, such as Bacillus thuringiensis or otherinsecticidal toxins, those expressing herbicide tolerance, such as“Roundup Ready” seed, or those with “stacked” foreign genes expressinginsecticidal toxins, herbicide tolerance, nutrition-enhancement, droughttolerance, or any other beneficial traits. Furthermore, such seedtreatments with molecules of Formula One may further enhance the abilityof a plant to withstand stressful growing conditions better. Thisresults in a healthier, more vigorous plant, which can lead to higheryields at harvest time. Generally, about 1 gram of such molecules toabout 500 grams per 100,000 seeds is expected to provide good benefits,amounts from about 10 grams to about 100 grams per 100,000 seeds isexpected to provide better benefits, and amounts from about 25 grams toabout 75 grams per 100,000 seeds is expected to provide even betterbenefits. Molecules of Formula One may be applied with one or moreactive ingredients in a soil amendment.

Molecules of Formula One may be used for controlling endoparasites andectoparasites in the veterinary medicine sector or in the field ofnon-human-animal keeping. Such molecules may be applied by oraladministration in the form of, for example, tablets, capsules, drinks,granules, by dermal application in the form of, for example, dipping,spraying, pouring on, spotting on, and dusting, and by parenteraladministration in the form of, for example, an injection.

Molecules of Formula One may also be employed advantageously inlivestock keeping, for example, cattle, chickens, geese, goats, pigs,sheep, and turkeys. They may also be employed advantageously in petssuch as, horses, dogs, and cats. Particular pests to control would beflies, fleas, and ticks that are bothersome to such animals. Suitableformulations are administered orally to the animals with the drinkingwater or feed. The dosages and formulations that are suitable depend onthe species.

Molecules of Formula One may also be used for controlling parasiticworms, especially of the intestine, in the animals listed above.

Molecules of Formula One may also be employed in therapeutic methods forhuman health care. Such methods include, but are limited to, oraladministration in the form of, for example, tablets, capsules, drinks,granules, and by dermal application.

Molecules of Formula One may also be applied to invasive pests. Pestsaround the world have been migrating to new environments (for such pest)and thereafter becoming a new invasive species in such new environment.Such molecules may also be used on such new invasive species to controlthem in such new environments.

The headings in this document are for convenience only and must not beused to interpret any portion hereof.

Tables

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LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20190150452A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1. A molecule having the following formula

wherein: (A) R¹ is selected from the group consisting of H, F, Cl, Br,I, CN, NO₂, SF₅, and (C₁-C₃)haloalkyl; (B) R² is selected from the groupconsisting of H, F, Cl, Br, I, CN, NO₂, SF₅, and (C₁-C₃)haloalkyl; (C)R³ is selected from the group consisting of H, F, Cl, Br, I, CN, NO₂,SF₅, and (C₁-C₃)haloalkyl; (D) R⁴ is selected from the group consistingof H, F, Cl, Br, I, CN, NO₂, SF₅, and (C₁-C₃)haloalkyl; (E) R⁵ isselected from the group consisting of H, F, Cl, Br, I, CN, NO₂, SF₅, and(C₁-C₃)haloalkyl; (F) R⁶ is H; (G) R⁷ is selected from the groupconsisting of F, Cl, and Br; (H) R⁸ is selected from the groupconsisting of F, Cl, and Br; (I) R⁹ is H; (J) Q¹ is selected from thegroup consisting of O and S; (K) Q² is selected from the groupconsisting of O and S; (L) R¹⁰ is selected from the group consisting ofH, (C₁-C₃) alkyl, (C₂-C₃)alkenyl, (C₂-C₃)alkynyl,(C₁-C₃)alkylO(C₁-C₃)alkyl, and (C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl; (M) R¹¹is selected from the group consisting of H, F, Cl, Br, I, CN, NO₂,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; (N) R¹² is selectedfrom the group consisting of H, F, Cl, Br, I, CN, NO₂, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; (O) R¹³ is selected from the groupconsisting of H, F, Cl, Br, I, CN, NO₂, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,and (C₁-C₃)alkoxy; (P) R¹⁴ is selected from the group consisting of H,F, Cl, Br, I, CN, NO₂, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and(C₁-C₃)alkoxy; (Q) X³ is: (1) N(R^(15a))(R^(15b)) wherein (a) saidR^(15a) is selected from the group consisting of H, (C₁-C₃)alkyl,(C₂-C₃)alkenyl, (C₂-C₃)alkynyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkylphenyl,(C₁-C₃)alkylO(C₁-C₃)alkyl, (C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl, andC(═O)(C₁-C₃)alkyl, and (b) said R^(15b) is a substituted orunsubstituted phenyl, said substituted phenyl has one or moresubstituents selected from the group consisting of H, F, Cl, Br, I, CN,NO₂, NH₂, OH, SF₅, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₂-C₃)alkenyl,(C₂-C₃)haloalkenyl, (C₁-C₃)alkoxy, (C═O)O(C₁-C₃)alkyl,O(C═O)(C₁-C₃)alkyl, N(R^(15c))₂, N═CHN(R^(15c))(X⁴),N(R^(15c))C(═O)O(X⁴), N(R^(15c))S(═O)₂(X⁴), N(S(═O)₂(C₁-C₃)alkyl)₂,N(R^(15c))C(═O)N(R^(15c))₂, N(R^(15c))C(═O)N(R^(15c))X⁴,N(R^(15c))C(═S)N(R^(15c))₂, N(R^(15c))C(═S)N(R^(15c))X⁴,N(R^(15c))(C₁-C₃)alkylX⁴, N(R^(15c))(CH(O(C₁-C₃)alkyl)₂),N(R^(15c))((C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl),N(R^(15c))((C₁-C₃)alkylC(═O)N(R^(15c))₂), N(R^(15c))C(═O)(R^(15c)),N(R^(15c))C(═O)X⁴, N(R^(15c))(C(═O))₂X⁴, N(R^(15c))(C(═O))₂OX⁴,N(R^(15c))(C(═O))₂N(R^(15c))X⁴, N(C(═O)O(C₁-C₆)alkyl)₂,N(R^(15c))C(═O)O(C₁-C₆)alkyl, N(R^(15c))C(═O)N(R^(15c))C(═O)O(R^(15c)),N(R^(15C))(C(═O)O(C₁-C₆)alkyl), N(R^(15c))(C(═O)O(C₁-C₆)haloalkyl),N((C₁-C₃)alkylOC(═O)(C₁-C₆)alkyl)(C(═O)(C₁-C₆)alkyl),N((C₁-C₃)alkylO(C₁-C₆)alkyl)(C(═O)O(C₁-C₆)alkyl),and N(R^(15c))C(═S)X⁴,(1) said R^(15c) is each independently selected from the groupconsisting of H, (C₁-C₃)alkyl, (C₂-C₃)alkenyl, (C₂-C₃)alkynyl,(C₁-C₃)haloalkyl, (C₂-C₃)haloalkenyl, (C₁-C₃)alkylphenyl,(C₁-C₃)alkylO(C₁-C₃)alkyl, (C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl,C(═O)(C₁-C₃)alkyl, and phenyl, optionally, for N(R^(15c))₂ saidN(R^(15c))₂ is a heterohydrocarbyl ring containing one nitrogen ringatom and three to five carbon ring atoms, where said ring may besaturated or unsaturated, (2) said X⁴ is selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₃)alkylO(C₁-C₃)alkyl,O(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkylphenyl, phenyl, aryl, andheterocyclyl, each of which may be substituted with one or more ofsubstituents selected from the group consisting of F, Cl, Br, I, CN, OH,NO₂, NH₂, oxo, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, NH(C₁-C₃)alkyl,N((C₁-C₃)alkyl)₂, O(C₁-C₆)alkyl, O(C₁-C₆)haloalkyl,N(R^(15c))C(═O)O(C₁-C₆)alkyl, N(R^(15c))S(═O)₂(R^(15c)),S(═O)₂(R^(15c)), (C₁-C₃)alkylO(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, wherein(1)(a) and (1)(b) each said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl,aryl, and heterocyclyl, may be substituted with one or more substituentsselected from the group consisting of F, Cl, Br, I, CN, OH, NO₂, NH₂,NH(C₁-C₃)alkyl, N((C₁-C₃)alkyl)₂, O(C₁-C₆)alkyl,(C₁-C₃)alkylO(C₁-C₃)alkyl, and (C₃-C₆)cycloalkyl; (2)N(R^(16a))(R^(16b)) wherein (a) said I:0⁶a is selected from the groupconsisting of H, (C₁-C₃)alkyl, (C₂-C₃)alkenyl, (C₂-C₃)alkynyl,(C₁-C₃)haloalkyl, (C₁-C₃)alkylO(C₁-C₃)alkyl,(C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl, and C(═O)(C₁-C₃)alkyl, (b) said R^(16b)is a substituted or unsubstituted (C₁-C₈)alkyl, said substituted(C₁-C₈)alkyl has one or more substituents selected from the groupconsisting of F, Cl, Br, I, CN, NO₂, O(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,(C₁-C₈)alkylphenyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, S(C₁-C₈)alkyl,S(O)(C₁-C₈)alkyl, S(O)₂(C₁-C₈)alkyl, Ophenyl, O(C₂-C₈)alkenyl,O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl, O(C₁-C₈)alkylphenyl,O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl, O(C₁-C₈)alkyl, C(═O)O(C₁-C₈)alkyl,OC(═O)(C₁-C₈)alkyl, C(═O)N(R^(16a))(C₁-C₈)alkyl,N(R^(16a))C(═O)(C₁-C₈)alkyl, S(C₁-C₈)alkyl, S(O)(C₁-C₈)alkyl,S(O)₂(C₁-C₈)alkyl, S(O)₂NH₂, and N(R^(16a))S(O)₂(C₁-C₈)alkyl, wherein(2)(a) and (2)(b) each alkyl, alkenyl, alkynyl, cycloalkyl, and phenyl,may be substituted with one or more substituents selected from the groupconsisting of F, Cl, Br, I, CN, OH, NH₂, NO₂, (C₁-C₈)alkyl,(C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, N((C₁-C₈)alkyl)₂, andC(═O)O(C₁-C₈)alkyl; (3) N(R^(17a))(N(R^(17b))(R^(17c)) wherein (a) saidR^(17a) is selected from the group consisting of H, (C₁-C₃)alkyl,(C₂-C₃)alkenyl, (C₂-C₃)alkynyl, (C₁-C₃)haloalkyl,(C₁-C₃)alkylO(C₁-C₃)alkyl, (C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl, andC(═O)(C₁-C₃)alkyl, (b) said R^(17b) is selected from the groupconsisting of H, (C₁-C₃)alkyl, (C₂-C₃)alkenyl, (C₂-C₃)alkynyl,(C₁-C₃)haloalkyl, (C₁-C₃)alkylO(C₁-C₃)alkyl,(C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl, and C(═O)(C₁-C₃)alkyl, (c) said R^(17c)is selected from the group consisting of H, substituted or unsubstitutedphenyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₃-C₈)cycloalkyl, C(═O)X⁵, and C(═S)X⁵, (1) said X⁵ is selected fromthe group consisting of substituted or unsubstituted phenyl, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted(C₁-C₈)alkyl, O(C₁-C₈)alkyl, O(C₁-C₈)haloalkyl, O(substituted andunsubstituted)phenyl, N(R^(17a))(C₁-C₈)alkyl,N(R^(17a))(C₁-C₈)haloalkyl, N(R^(17a))(C₃-C₈)cycloalkyl, N(R^(17a))(substituted and unsubstituted phenyl), and (C₃-C₆)cycloalkyl, (2) saidsubstituted phenyl in (3)(c) has one or more substituents selected fromthe group consisting of F, Cl, Br, I, CN, NO₂, OH, (C₁-C₃)alkoxy, and(C₁-C₃)alkyl, (3) said substituted heterocyclyl in (3)(c) has one ormore substituents selected from the group consisting of F, Cl, Br, I,CN, NO₂, OH, (C₁-C₃)alkoxy, and (C₁-C₃)alkyl, (4) said substituted(C₁-C₈)alkyl in (3)(c) has one or more substituents selected from thegroup consisting of F, Cl, Br, I, CN, OH, NO₂, NH₂, O(C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, phenyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,S(C₁-C₈)alkyl, S(O)(C₁-C₈)alkyl, S(O)₂(C₁-C₈)alkyl, Ophenyl,O(C₂-C₈)alkenyl, O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl, O(C₁-C₈)alkylphenyl,O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl, C(═O)NH(C₁-C₈)alkyl,NHC(═O)(C₁-C₈)alkyl, S(O)₂NH₂, NH(C₁-C₃)alkyl, N((C₁-C₃)alkyl)₂, (5)said substituted (C₃-C₈)cycloalkyl has one or more substituents selectedfrom the group consisting of F, Cl, Br, I, CN, OH, (C₁-C₃)alkoxy, and(C₁-C₃)alkyl, wherein (2)(a), (2)(b), and (2)(c) each alkyl, alkenyl,alkynyl, cycloalkyl, haloalkyl, phenyl, and heterocyclyl, may beoptionally substituted with one or more substituents selected from thegroup consisting of F, Cl, Br, I, CN, OH, NH₂, NO₂, (C₁-C₈)alkyl,(C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, N((C₁-C₈)alkyl)₂, andC(═O)O(C₁-C₈)alkyl, optionally (N(R^(17b))(R^(16c)) is aheterohydrocarbyl ring containing one nitrogen ring atom and three tofive carbon ring atoms, where said ring may be saturated or unsaturated;(4) N(R^(18a))(N═C(R^(18b))(R^(18c)) (a) said R^(18a) is selected fromthe group consisting of H, (C₁-C₃)alkyl, (C₂-C₃)alkenyl, (C₂-C₃)alkynyl,(C₁-C₃)alkylO(C₁-C₃)alkyl, (C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl, andC(═O)(C₁-C₃)alkyl, (b) said R^(18b) is selected from the groupconsisting of H and (C₁-C₃)alkyl, (c) said R^(18c) is selected from thegroup consisting of substituted or unsubstituted phenyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted (C₁-C₈)alkyl,substituted or unsubstituted (C₃-C₈)cycloalkyl, (1) said substitutedphenyl in (4)(c) has one or more substituents selected from the groupconsisting of F, Cl, Br, I, CN, NO₂, OH, (C₁-C₃)alkoxy, (C₁-C₃)alkyl,(C₁-C₃)haloalkoxy, and (C₁-C₃)haloalkyl, (2) said substitutedheterocyclyl in (4)(c) has one or more substituents selected from thegroup consisting of F, Cl, Br, I, CN, NO₂, OH, (C₁-C₃)alkoxy,(C₁-C₃)alkyl, (C₁-C₃)haloalkoxy, and (C₁-C₃)haloalkyl, (3) saidsubstituted (C₁-C₈)alkyl has one or more substituents selected from thegroup consisting of F, Cl, Br, I, CN, NO₂, O(C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, phenyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,S(C₁-C₈)alkyl, S(O)(C₁-C₈)alkyl, S(O)₂(C₁-C₈)alkyl, Ophenyl,O(C₂-C₈)alkenyl, O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl, O(C₁-C₈)alkylphenyl,O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl, C(═O)NH(C₁-C₈)alkyl,NHC(═O)(C₁-C₈)alkyl, and S(O)₂NH₂, (4) said substituted(C₃-C₈)cycloalkyl has one or more substituents selected from the groupconsisting of F, Cl, Br, I, CN, OH, (C₁-C₃)alkoxy, and (C₁-C₃)alkyl,wherein (4)(a), (4)(b), and (4)(c) each alkyl, alkenyl, alkynyl,cycloalkyl, haloalkyl, phenyl, and heterocyclyl may be substituted withone or more substituents selected from the group consisting of F, Cl,Br, I, CN, OH, NH₂, NO₂, (C₁-C₈)alkyl, (C₁-C₈)alkoxy, (C₁-C₈)haloalkyl,N((C₁-C₈)alkyl)₂, and C(═O)O(C₁-C₈)alkyl, optionally C(R^(18b))(R^(18c))is a hydrocarbyl ring containing three to five carbon ring atoms, wheresaid ring may be saturated or unsaturated, optionally, one or more ofsaid carbon ring atoms may instead be nitrogen, oxygen, or sulfur atom;and N-oxides, agriculturally acceptable acid addition salts, saltderivatives, solvates, ester derivatives, crystal polymorphs, isotopes,resolved stereoisomers, tautomers, pro-insecticides, of the molecules ofFormula One.
 2. A molecule according to claim 1 wherein: (A) R¹ isselected from the group consisting of H, F, Cl, Br, I, CN, NO₂, SF₅, and(C₁-C₃)haloalkyl; (B) R² is selected from the group consisting of H, F,Cl, Br, I, CN, NO₂, SF₅, and (C₁-C₃)haloalkyl; (C) R³ is selected fromthe group consisting of H, F, Cl, Br, I, CN, NO₂, SF₅, and(C₁-C₃)haloalkyl; (D) R⁴ is selected from the group consisting of H, F,Cl, Br, I, CN, NO₂, SF₅, and (C₁-C₃)haloalkyl; (E) R⁵ is selected fromthe group consisting of H, F, Cl, Br, I, CN, NO₂, SF₅, and(C₁-C₃)haloalkyl; (F) R⁶ is H; (G) R⁷ is selected from the groupconsisting of F, Cl, and Br; (H) R⁸ is selected from the groupconsisting of F, Cl, and Br; (I) R⁹ is H; (J) Q¹ is selected from thegroup consisting of O and S; (K) Q² is selected from the groupconsisting of O and S; (L) R¹⁰ is selected from the group consisting ofH, (C₁-C₃) alkyl, (C₂-C₃)alkenyl, (C₂-C₃)alkynyl,(C₁-C₃)alkylO(C₁-C₃)alkyl, and (C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl; (M) R¹¹is selected from the group consisting of H, F, Cl, Br, I, CN, NO₂,(C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; (N) R¹² is selectedfrom the group consisting of H, F, Cl, Br, I, CN, NO₂, (C₁-C₃)alkyl,(C₁-C₃)haloalkyl, and (C₁-C₃)alkoxy; (O) R¹³ is selected from the groupconsisting of H, F, Cl, Br, I, CN, NO₂, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl,and (C₁-C₃)alkoxy; (P) R¹⁴ is selected from the group consisting of H,F, Cl, Br, I, CN, NO₂, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, and(C₁-C₃)alkoxy; (Q) X³ is: (1) N(R^(15a))(R^(15b)) wherein (a) saidR^(15a) is selected from the group consisting of H, (C₁-C₃)alkyl,(C₂-C₃)alkenyl, (C₂-C₃)alkynyl, (C₁-C₃)haloalkyl, (C₁-C₃)alkylphenyl,(C₁-C₃)alkylO(C₁-C₃)alkyl, (C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl, andC(═O)(C₁-C₃)alkyl, and (b) said R^(15b) is a substituted orunsubstituted phenyl, said substituted phenyl has one or moresubstituents selected from the group consisting of H, F, Cl, Br, I, CN,NO₂, NH₂, OH, SF₅, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, (C₂-C₃)alkenyl,(C₂-C₃)haloalkenyl, (C₁-C₃)alkoxy, (C═O)O(C₁-C₃)alkyl,O(C═O)(C₁-C₃)alkyl, N(R^(15c))₂, N═CHN(R^(15C))(X⁴),N(R^(15c))C(═O)O(X⁴), N(R^(15c))S(═O)₂(X⁴), N(S(═O)₂(C₁-C₃)alkyl)₂,N(R^(15c))═O)N(R^(15c))₂, N(R^(15c))C(═O)N(R^(15c))X⁴,N(R^(15c))C(═S)N(R^(15c))₂, N(R^(15c))C(═S)N(R^(15c))X⁴,N(R^(15c))(C₁-C₃)alkylX⁴, N(R^(15c))(CH(O(C₁-C₃)alkyl)₂),N(R^(15c))((C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl),N(R^(15c))((C₁-C₃)alkylC(═O)N(R^(15c))₂), N(R^(15c))C(═O)(R^(15c)),N(R^(15c))C(═O)X⁴, N(R^(15c))(C(═O))₂X⁴, N(R^(15c))(C(═O))₂OX⁴,N(R^(15c))(C(═O))₂N(R^(15c))X⁴, N(C(═O)O(C₁-C₆)alkyl)₂,N(R^(15c))C(═O)O(C₁-C₆)alkyl, N(R^(15c))C(═O)N(R^(15c))C(═O)O(R^(15c)),N(R^(15c))(C(═O)O(C₁-C₆)alkyl), N(R^(15c))(C(═O)O(C₁-C₆)haloalkyl),N((C₁-C₃)alkylOC(═O)(C₁-C₆)alkyl)(C(═O)(C₁-C₆)alkyl),N((C₁-C₃)alkylO(C₁-C₆)alkyl)(C(═O)O(C₁-C₆)alkyl),and N(R^(15c))C(═S)X⁴,(1) said R^(15c) is each independently selected from the groupconsisting of H, (C₁-C₃)alkyl, (C₂-C₃)alkenyl, (C₂-C₃)alkynyl,(C₁-C₃)haloalkyl, (C₂-C₃)haloalkenyl, (C₁-C₃)alkylphenyl,(C₁-C₃)alkylO(C₁-C₃)alkyl, (C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl,C(═O)(C₁-C₃)alkyl, and phenyl, optionally, for N(R^(15c))₂ saidN(R^(15c))₂ is a heterohydrocarbyl ring containing one nitrogen ringatom and three to five carbon ring atoms, where said ring may besaturated or unsaturated, (2) said X⁴ is selected from the groupconsisting of (C₁-C₆)alkyl, (C₁-C₆)haloalkyl, (C₁-C₃)alkylO(C₁-C₃)alkyl,O(C₁-C₆)alkyl, (C₃-C₆)cycloalkyl, (C₁-C₆)alkylphenyl, phenyl, aryl, andheterocyclyl, each of which may be substituted with one or more ofsubstituents selected from the group consisting of F, Cl, Br, I, CN, OH,NO₂, NH₂, oxo, (C₁-C₃)alkyl, (C₁-C₃)haloalkyl, NH(C₁-C₃)alkyl,N((C₁-C₃)alkyl)₂, O(C₁-C₆)alkyl, O(C₁-C₆)haloalkyl,N(R^(15c))C(═O)O(C₁-C₆)alkyl, N(R^(15c))S(═O)₂(R^(15c)),S(═O)₂(R^(15c)), (C₁-C₃)alkylO(C₁-C₃)alkyl, (C₃-C₆)cycloalkyl, wherein(1)(a) and (1)(b) each said alkyl, alkenyl, alkynyl, cycloalkyl, phenyl,aryl, and heterocyclyl, may be substituted with one or more substituentsselected from the group consisting of F, Cl, Br, I, CN, OH, NO₂, NH₂,NH(C₁-C₃)alkyl, N((C₁-C₃)alkyl)₂, O(C₁-C₆)alkyl,(C₁-C₃)alkylO(C₁-C₃)alkyl, and (C₃-C₆)cycloalkyl; (2)N(R^(16a))(R^(16b)) wherein (a) said R^(16a) is selected from the groupconsisting of H, (C₁-C₃)alkyl, (C₂-C₃)alkenyl, (C₂-C₃)alkynyl,(C₁-C₃)haloalkyl, (C₁-C₃)alkylO(C₁-C₃)alkyl,(C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl, and C(═O)(C₁-C₃)alkyl, (b) said R^(16b)is a substituted or unsubstituted (C₁-C₈)alkyl, said substituted(C₁-C₈)alkyl has one or more substituents selected from the groupconsisting of F, Cl, Br, I, CN, NO₂, O(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl,(C₁-C₈)alkylphenyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, S(C₁-C₈)alkyl,S(O)(C₁-C₈)alkyl, S(O)₂(C₁-C₈)alkyl, Ophenyl, O(C₂-C₈)alkenyl,O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl, O(C₁-C₈)alkylphenyl,O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl, O(C₁-C₈)alkyl, C(═O)O(C₁-C₈)alkyl,OC(═O)(C₁-C₈)alkyl, C(═O)N(R^(16a))(C₁-C₈)alkyl,N(R^(16a))C(═O)(C₁-C₈)alkyl, S(C₁-C₈)alkyl, S(O)(C₁-C₈)alkyl,S(O)₂(C₁-C₈)alkyl, S(O)₂NH₂, and N(R^(16a))S(O)₂(C₁-C₈)alkyl, wherein(2)(a) and (2)(b) each alkyl, alkenyl, alkynyl, cycloalkyl, and phenyl,may be substituted with one or more substituents selected from the groupconsisting of F, Cl, Br, I, CN, OH, NH₂, NO₂, (C₁-C₈)alkyl,(C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, N((C₁-C₈)alkyl)₂, andC(═O)O(C₁-C₈)alkyl; (3) N(R^(17a))(N(R^(17b))(R^(17c))) wherein (a) saidR^(17a) is selected from the group consisting of H, (C₁-C₃)alkyl,(C₂-C₃)alkenyl, (C₂-C₃)alkynyl, (C₁-C₃)haloalkyl,(C₁-C₃)alkylO(C₁-C₃)alkyl, (C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl, andC(═O)(C₁-C₃)alkyl, (b) said R^(17b) is selected from the groupconsisting of H, (C₁-C₃)alkyl, (C₂-C₃)alkenyl, (C₂-C₃)alkynyl,(C₁-C₃)haloalkyl, (C₁-C₃)alkylO(C₁-C₃)alkyl,(C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl, and C(═O)(C₁-C₃)alkyl, (c) said R^(17c)is selected from the group consisting of H, substituted or unsubstitutedphenyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₃-C₈)cycloalkyl, C(═O)X⁵, and C(═S)X⁵, (1) said X⁵ is selected fromthe group consisting of substituted or unsubstituted phenyl, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted(C₁-C₈)alkyl, O(C₁-C₈)alkyl, O(C₁-C₈)haloalkyl, O(substituted andunsubstituted)phenyl, N(R^(17a))(C₁-C₈)alkyl,N(R^(17a))(C₁-C₈)haloalkyl, N(R^(17a))(C₃-C₈)cycloalkyl, N(R^(17a))(substituted and unsubstituted phenyl), and (C₃-C₆)cycloalkyl, (2) saidsubstituted phenyl in (3)(c) has one or more substituents selected fromthe group consisting of F, Cl, Br, I, CN, NO₂, OH, (C₁-C₃)alkoxy, and(C₁-C₃)alkyl, (3) said substituted heterocyclyl in (3)(c) has one ormore substituents selected from the group consisting of F, Cl, Br, I,CN, NO₂, OH, (C₁-C₃)alkoxy, and (C₁-C₃)alkyl, (4) said substituted(C₁-C₈)alkyl in (3)(c) has one or more substituents selected from thegroup consisting of F, Cl, Br, I, CN, OH, NO₂, NH₂, O(C₁-C₈)alkyl,(C₃-C₈)cycloalkyl, phenyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,S(C₁-C₈)alkyl, S(O)(C₁-C₈)alkyl, S(O)₂(C₁-C₈)alkyl, Ophenyl,O(C₂-C₈)alkenyl, O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl, O(C₁-C₈)alkylphenyl,O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl, C(═O)NH(C₁-C₈)alkyl,NHC(═O)(C₁-C₈)alkyl, S(O)₂NH₂, NH(C₁-C₃)alkyl, N((C₁-C₃)alkyl)₂, (5)said substituted (C₃-C₈)cycloalkyl has one or more substituents selectedfrom the group consisting of F, Cl, Br, I, CN, OH, (C₁-C₃)alkoxy, and(C₁-C₃)alkyl, wherein (2)(a), (2)(b), and (2)(c) each alkyl, alkenyl,alkynyl, cycloalkyl, haloalkyl, phenyl, and heterocyclyl, may beoptionally substituted with one or more substituents selected from thegroup consisting of F, Cl, Br, I, CN, OH, NH₂, NO₂, (C₁-C₈)alkyl,(C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, N((C₁-C₈)alkyl)₂, andC(═O)O(C₁-C₈)alkyl, optionally (N(R^(17b))(R^(17c))) is aheterohydrocarbyl ring containing one nitrogen ring atom and three tofive carbon ring atoms, where said ring may be saturated or unsaturated;and (4) N(R^(18a))(N═C(R^(18b))(R^(18c)) (a) said R^(18a) is selectedfrom the group consisting of H, (C₁-C₃)alkyl, (C₂-C₃)alkenyl,(C₂-C₃)alkynyl, (C₁-C₃)alkylO(C₁-C₃)alkyl,(C₁-C₃)alkylOC(═O)(C₁-C₃)alkyl, and C(═O)(C₁-C₃)alkyl, (b) said R^(18b)is selected from the group consisting of H and (C₁-C₃)alkyl, (c) saidR^(18c) is selected from the group consisting of substituted orunsubstituted phenyl, substituted or unsubstituted heterocyclyl,substituted or unsubstituted (C₁-C₈)alkyl, substituted or unsubstituted(C₃-C₈)cycloalkyl, (1) said substituted phenyl in (4)(c) has one or moresubstituents selected from the group consisting of F, Cl, Br, I, CN,NO₂, OH, (C₁-C₃)alkoxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkoxy, and(C₁-C₃)haloalkyl, (2) said substituted heterocyclyl in (4)(c) has one ormore substituents selected from the group consisting of F, Cl, Br, I,CN, NO₂, OH, (C₁-C₃)alkoxy, (C₁-C₃)alkyl, (C₁-C₃)haloalkoxy, and(C₁-C₃)haloalkyl, (3) said substituted (C₁-C₈)alkyl has one or moresubstituents selected from the group consisting of F, Cl, Br, I, CN,NO₂, O(C₁-C₈)alkyl, (C₃-C₈)cycloalkyl, phenyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, S(C₁-C₈)alkyl, S(O)(C₁-C₈)alkyl, S(O)₂(C₁-C₈)alkyl,Ophenyl, O(C₂-C₈)alkenyl, O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl,O(C₁-C₈)alkylphenyl, O(C₁-C₈)alkyl(C₃-C₈)cycloalkyl,C(═O)NH(C₁-C₈)alkyl, NHC(═O)(C₁-C₈)alkyl, and S(O)₂NH₂, (4) saidsubstituted (C₃-C₈)cycloalkyl has one or more substituents selected fromthe group consisting of F, Cl, Br, I, CN, OH, (C₁-C₃)alkoxy, and(C₁-C₃)alkyl, wherein (4)(a), (4)(b), and (4)(c) each alkyl, alkenyl,alkynyl, cycloalkyl, haloalkyl, phenyl, and heterocyclyl may besubstituted with one or more substituents selected from the groupconsisting of F, Cl, Br, I, CN, OH, NH₂, NO₂, (C₁-C₈)alkyl,(C₁-C₈)alkoxy, (C₁-C₈)haloalkyl, N((C₁-C₈)alkyl)₂, andC(═O)O(C₁-C₈)alkyl, optionally C(R^(18b))(R^(18c)) is a hydrocarbyl ringcontaining three to five carbon ring atoms, where said ring may besaturated or unsaturated, optionally, one or more of said carbon ringatoms may instead be nitrogen, oxygen, or sulfur atom.
 3. A moleculeaccording to claim 2 wherein said molecule has the following formula


4. A molecule according to claim 3 wherein R¹, R², R³, R⁴, R⁵ are eachindependently selected from the group consisting of H, F, Cl, Br, SF₅,and CF₃.
 5. A molecule according to claim 3 wherein R⁷ and R⁸ is Cl. 6.A molecule according to claim 3 wherein R⁷, and R⁸ are not the same. 7.A molecule according to claim 3 wherein R¹² is selected from the groupconsisting of H, F, Cl, CH₃, and CF₃.
 8. A molecule according to claim 3wherein R¹³ is selected from the group consisting of F, Cl, CH₃, andOCH₃.
 9. A molecule according to claim 3 wherein R¹⁴ is selected fromthe group consisting of H, F, and Cl.
 10. A molecule according to claim3 wherein: R¹ is selected from the group consisting of H, F, Cl, Br,SF₅, and CF₃; R² is selected from the group consisting of H, F, Cl, Br,SF₅, and CF₃; R³ is selected from the group consisting of H, F, Cl, Br,SF₅, and CF₃; R⁴ is selected from the group consisting of H, F, Cl, Br,SF₅, and CF₃; R⁵ is selected from the group consisting of H, F, Cl, Br,SF₅, and CF₃; R⁷ is Cl; R⁸ is Cl; Q¹ is O; Q² is O; R¹⁰ is H; R¹¹ is H;R¹² is selected from the group consisting of H, F, Cl, CH₃, and CF₃; R¹³is selected from the group consisting of F, Cl, CH₃, and OCH₃; and R¹⁴is selected from the group consisting of H, F, and Cl.
 11. A moleculeaccording to claim 3 wherein X³ is N(R^(15a))(R^(15b)).
 12. A moleculeaccording to claim 3 wherein X³ is N(R^(16a))(R^(16b)).
 13. A moleculeaccording to claim 3 wherein X³ is N(R^(17a))(N(R^(17b))(R^(17c)).
 14. Amolecule according to claim 3 wherein X³ isN(R^(18a))(N═C(R^(18b))(R^(18c)).
 15. A molecule selected from Table 2.16. A composition comprising a molecule according to claim 3 furthercomprising an active ingredient.
 17. A composition according to claim 16wherein the weight ratio of the molecule according to Formula Two to theactive ingredient is 100:1 to 1:100.
 18. A composition according toclaim 16 wherein the weight ratio of the molecule of Formula Two to theactive ingredient is X:Y; wherein X is the parts by weight of themolecule of Formula Two and Y is the parts by weight of the activeingredient; further wherein the numerical range of the parts by weightfor X is 0<X≤100 and the parts by weight for Y is 0<Y≤100; and furtherwherein X and Y are selected from Table C.
 19. A seed treated with amolecule according to claim
 3. 20. A process to control a pest saidprocess comprising applying to a locus, a pesticidally effective amountof a molecule according to claim 3.